Cycloalkane[b]indole antagonists of prostaglandin d2 receptors

ABSTRACT

Described herein are compounds that are antagonists of PGD 2  receptors. Also described are pharmaceutical compositions and medicaments that include the compounds described herein that are antagonists of PGD 2  receptors. Also described herein are methods of using such antagonists of PGD 2  receptors, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other PGD 2 -dependent or PGD 2 -mediated conditions or diseases.

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patent application No. 61/075,242 entitled “CYCLOALKANE[B]INDOLE ANTAGONISTS OF PROSTAGLANDIN D₂ RECEPTORS” filed on Jun. 24, 2008, which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders or conditions associated with prostaglandin D₂.

BACKGROUND OF THE INVENTION

Prostaglandins are acidic lipids derived from the metabolism of arachidonic acid by the action of cyclooxygenase enzymes and downstream synthases. Prostaglandins have a diverse range of activities and have a well recognized role in pain and inflammation. Prostaglandin D₂ (PGD₂) is an acidic lipid mediator derived from the metabolism of arachidonic acid by cyclooxygenases and PGD₂ synthases. PGD₂ is produced by mast cells, macrophages and Th2 lymphocytes in response to local tissue damage as well as allergic inflammation in diseases such as asthma, rhinitis, and atopic dermatitis. Exogenous PGD₂ applied to bronchial airways elucidates many characteristics of an asthmatic response suggesting that PGD₂ plays an important pro-inflammatory role in allergic diseases.

PGD₂ binds to a number of receptors, which include the thromboxane-type prostanoid (TP) receptor, PGD₂ receptor (DP, also known as DP₁) and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2; also known as DP₂). DP₂ is associated with promoting chemotaxis and activation of Th2 lymphocytes, eosinophils and basophils. In particular, PGD₂ binds to DP₂, and mediates its effects through a G₁-dependant elevation in calcium levels and reduction of intracellular cyclic AMP. In Th2 lymphocytes, IL4, IL5 and IL13 cytokine production is stimulated. These cytokines have been implicated in numerous biological actions including, by way of example only, immunoglobulin E production, airway response, mucous secretion, and eosinophil recruitment.

SUMMARY OF THE INVENTION

Presented herein are compounds, pharmaceutical compositions and medicaments, methods, for (a) diagnosing, preventing, or treating allergic and non-allergic inflammation, (b) mitigating adverse signs and symptoms that are associated with inflammation, and/or (c) controlling immunological, proliferative or metabolic disorders. These disorders may arise from one or more of a genetic, iatrogenic, immunological, infectious, metabolic, oncological, toxic, surgical, and/or traumatic etiology. In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein comprise antagonists of PGD₂ receptors. In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein comprise antagonists of DP₂.

In some embodiments provided herein are compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, which are antagonists of DP₂, and are used to treat subjects suffering from one or more PGD₂-dependent conditions or diseases, including, but not limited to, asthma, rhinitis, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory conditions. In some embodiments, PGD₂-dependent conditions or diseases include those wherein an absolute or relative excess of PGD₂ is present and/or observed.

In some embodiments provided herein is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

-   -   wherein,     -   R¹, R², R³, and R⁴ each are independently selected from H,         halogen, —CN, —NO₂, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹²,         —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —C(═O)R¹², —OC(═O)R¹², —CO₂R¹³,         —OCO₂R¹², —N(R¹³)₂, —C(═O)N(R¹³)₂, —OC(═O)N(R¹³)₂, —NHC(═O)R¹²,         —NHC(═O)OR¹², C₁-C₆alkyl, C_(I)-C₆fluoroalkyl,         C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, an optionally         substituted cycloalkyl, an optionally substituted         heterocycloalkyl, optionally substituted phenyl, and an         optionally substituted monocyclic heteroaryl;     -   R⁵ is L⁵-X⁵;         -   L⁵ is —C₁-C₆alkyl-, -C₁-C₆flouroalkyl-, or             —C₃-C₆cycloalkyl-, —C₁-C₆alkyl-(an optionally substituted             aryl)-, —C₁-C₆alkyl-(an optionally substituted heteroaryl)-,             an an optionally substituted aryl, or an optionally             substituted heteroaryl;         -   X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂,             —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹²,             —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹²,             —OH, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂,             —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or             —C(═NR¹⁴)N(R¹³)₂;     -   R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, an         optionally substituted cycloalkyl, an optionally substituted         heterocycloalkyl, an optionally substituted aryl, an optionally         substituted heteroaryl, —C₁-C₆alkyl-(an optionally substituted         cycloalkyl), —C₁-C₆alkyl-(an optionally substituted         heterocycloalkyl), —C₁-C₆alkyl-(an optionally substituted aryl),         or —C₁-C₆alkyl-(an optionally substituted heteroaryl);     -   R⁷ is L⁷-X⁷;         -   L⁷ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, or an optionally             substituted C₃-C₆cycloalkyl;         -   X⁷ is —CO₂H, —CO₂R¹², —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂,             —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹²,             —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹²,             —OH, —OR¹², —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂,             —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or             —C(═NR¹⁴)N(R¹³)₂;     -   each R⁸ and R⁹ is independently selected from H, C₁-C₄alkyl, and         C₁-C₄haloalkyl; or     -   two R⁸ groups are taken together with the carbon atom to which         they are attached to form a carbonyl (—C(═O)—); or     -   both R⁹ groups are taken together with the carbon atom to which         they are attached to form a carbonyl (—C(═O)—);     -   R¹⁰ is H, C₁-C₄alkyl, C₁-C₄haloalkyl, or -L¹⁰-X¹⁰;         -   L¹⁰- is —C₁-C₆alkyl-, —C₃-C₆cycloalkyl-, —C₁-C₆alkyl-(an             optionally substituted aryl)- or —C₁-C₆alkyl-(an optionally             substituted heteroaryl)-;         -   X¹⁰ is —CO₂R¹³, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH,             —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂,             —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OR¹³, —SR¹²,             —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹²,             —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)_(N)(R¹³)₂;     -   R¹² is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl,         optionally substituted cycloalkyl, optionally substituted         heterocycloalkyl, optionally substituted aryl, optionally         substituted benzyl or optionally substituted heteroaryl;     -   each R¹³ is independently selected from H, C₁-C₆alkyl,         C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, an optionally substituted         cycloalkyl, an optionally substituted heterocycloalkyl, an         optionally substituted aryl, an optionally substituted benzyl,         and an optionally substituted heteroaryl;     -   two R¹³ groups attached to the same N atom are taken together         with the N atom to which they are attached to form an optionally         substituted heterocycloalkyl;     -   R¹⁴ is selected from among H, —S(═O)₂R¹², —S(═O)₂NH₂, —C(═O)R¹²,         —CN, and —NO₂;     -   m is 1, 2, or 3.

For any and all of the embodiments, substituents can be selected from among from a subset of the listed alternatives. For example, in some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OH, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OH, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —SR¹², —S(═O)R¹², —S(═O)₂R¹², or —N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, or —N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —S(═O)₂N(R¹³)₂, or —OH. In some embodiments, X⁵ is —CO₂R¹³, —C(═O)N(R¹³)₂, or —OH.

In some embodiments, each R⁸ and R⁹ is each independently selected from H, or —CH₃; or two R⁸ groups are taken together with the carbon atom to which they are attached to form a carbonyl(-C(═O)—); or both R⁹ groups are taken together with the carbon atom to which they are attached to form a carbonyl(-C(═O)—); and m is 1 or 2. In some embodiments, each R⁸ and R⁹ is H.

In some embodiments, R¹, R², R³, and R⁴ each are independently selected from H, halogen, —CN, —NO₂, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —S (═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —C(═O)R¹², —OC(═O)R¹², —CO₂R¹³, —OCO₂R¹², —N(R¹³)₂, —C(═O)N(R¹³)₂, —OC(═O)N(R¹³)₂, —NHC(═O)R¹², —NHC(═O)OR¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, optionally substituted phenyl, and an optionally substituted monocyclic heteroaryl, provided that at least two of R¹, R², R³, and R⁴ are H.

In some embodiments, R¹, R², R³, and R⁴ each are independently selected from H, halogen, —CN, —OH, —OR¹³, —S(═O)₂C₁-C₆alkyl, —S(═O)₂N(R¹³)₂, —NHS(═O)₂R¹², —OC(═O)R¹², —C(═O)N(R¹³)₂, —NHC(═O)R¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl. In some embodiments, R¹, R², R³, and R⁴ each are independently selected from H, halogen, —CN, —OH, —OR¹³, —S(═O)₂C₁-C₆alkyl, —S(═O)₂N(R¹³)₂, —NHS(═O)₂R¹², —OC(═O)R¹², —C(═O)N(R¹³)₂, —NHC(═O)R¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl, provided that at least two of R¹, R², R³, and R⁴ are H.

In some embodiments, R¹, R², R³, and R⁴ each are independently selected from H, halogen, —CN, —OH, —S(═O)₂C₁-C₆alkyl, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, C₁-C₄alkoxy, and C₁-C₄heteroalkyl.

In some embodiments, at least two of R¹, R², R³, and R⁴ is H. In some embodiments, at least three of R¹, R², R³, and R⁴ is H. In some embodiments, each of R¹, R², R³, and R⁴ is H.

In some embodiments, R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, an optionally substituted C₃-C₁₀cycloalkyl, an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl containing 0-3 N atoms, an optionally substituted —C₁-C₆alkyl-cycloalkyl, an optionally substituted —C₁-C₆alkyl-phenyl, or an optionally substituted —C₁-C₆alkyl-(monocyclic heteroaryl).

In some embodiments, R⁶ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl containing 0-3 N atoms.

In some embodiments, R⁶ is an optionally substituted C₃-C₁₀cycloalkyl, an optionally substituted C₂-C₁₀heterocycloalkyl, an optionally substituted phenyl, an optionally substituted napthyl, an optionally substituted monocyclic heteroaryl containing 0-3 N atoms.

In some embodiments, L⁷ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, or an optionally substituted C₃-C₆cycloalkyl; X⁷ is —CO₂R¹³, —C(═O)N(R¹³)₂, tetrazolyl, —OH, or —C(═O)NHC(═O)R¹². In some embodiments, L⁷ is C₁-C₆alkyl. In some embodiments, L⁷ is C₁-C₄alkyl.

In some embodiments, L⁵ is —C₁-C₆alkyl, or —C₁-C₆alkyl-(an optionally substituted phenyl); and X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², or —N(R¹³)₂. In some embodiments, L⁵ is —C₁-C₆alkyl.

In some embodiments, L⁵ is C₁-C₆alkyl; X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —OR¹³, —SR¹², —S(═O)₂R¹², or —N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —S(═O)₂R¹², or —N(R¹³)₂.

In some sembodiments, L⁷ is C₁-C₆alkyl; X⁷ is CO₂H, —CO₂(C₁-C₆alkyl), or —OH. In some sembodiments, X⁷ is CO₂H, or —OH.

In some embodiments, R¹⁰ is H or C₁-C₄alkyl.

In some embodiments, each of R⁸ and R⁹ is H.

In some embodiments, the compound of Formula (I) has the following structure:

In some embodiments, m is 1.

In some embodiments, the compound of Formula (I) has the structure of Formula (II):

In some embodiments, m is 2.

In some embodiments, the compound of Formula (I) has the structure of Formula (II):

In some embodiments, R¹⁰ is H or —CH₃. In some embodiments, R¹⁰ is H. In some embodiments, R¹⁰ is —CH₃.

In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —OH, or —OR¹³. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, or —OH. In some embodiments, X⁵ is —CO₂R¹³, —C(═O)N(R¹³)₂, or —OH.

In some embodiments, R¹, R², R³, and R⁴ each are independently selected from H, F, Cl, Br, I, —CN, —OH, —OCH₃, —S(═O)₂CH₃, —CH₃, and —CF₃; and R¹⁰ is H. In some embodiments, R¹, R², R³, and R⁴ are independently selected from H, F, Cl, Br, I, —CN, −OH, —OCH₃, —S(═O)₂CH₃, —CH₃, and —CF₃, provided that at least two of R¹, R², R³, and R⁴ are H. In one aspect, each of R¹, R², R³, and R⁴ are H.

In some embodiments, R⁷ is —CH₂CO₂H, —CH₂CH₂CO₂H, —C(CH₃)₂OH, —CH₂C(CH₃)₂OH, or —CH₂CH₂C(CH₃)₂OH.

In some embodiments, R⁵ is —CH₂CH₂OH, —CH₂CO₂H, —CH₂CH(CH₃)OH, —CH₂C(CH₃)₂OH, —CH₂CH₂OH, —(CH₂)₂CO₂H, —CH₂-tetrazolyl, —CH₂C(═O)NH₂, or —(CH₂)₂C(═O)NH₂.

In some embodiments, R⁵ is —CH₂CO₂H, —CH₂C(CH₃)₂OH, or —CH₂C(═O)NH₂.

In some embodiments, R⁶ is an optionally substituted phenyl. In some embodiments, R⁶ is an optionally substituted phenyl, where if the phenyl is susbtituted then the phenyl is substituted with one or two groups selected from F, Cl, Br, I, —CN, —OH, —OCH₃, —S(═O)₂CH₃, —CH₃, and —CF₃. In some embodiments, R⁶ is an optionally substituted phenyl, where if the phenyl is susbtituted then the phenyl is substituted with F, Cl, Br, I, —CN, —OH, —OCH₃, —S(═O)₂CH₃, —CH₃, or —CF₃. In some embodiments, R⁶ is 4-fluorophenyl.

Any combination of the groups described above for the various variables is contemplated herein.

In some embodiments, the compound of Formula (I) is selected from among: {3-[Carboxymethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-acetic acid (Compound 1-1); {(4-Fluoro-benzenesulfonyl)-[9-(3-hydroxy-3-methyl-butyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino}-acetic acid (Compound 1-2); 3-{3-[(4-Fluoro-benzenesulfonyl)-(2-hydroxy-2-methyl-propyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionic acid (Compound 1-3); 4-FluoroN-[9-(3-hydroxy-3-methyl-butyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N-(2-hydroxy-2-methyl-propyl)-benzenesulfonamide (Compound 1-4); 3-{3-[Carbamoylmethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionic acid (Compound 1-5); and 3-{3-[Carboxymethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionic acid (Compound 1-6).

Also provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of any of Formulas (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable inactive ingredient selected from pharmaceutically acceptable diluents, pharmaceutically acceptable excipients, and pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, buccal administration, transdermal administration, nasal administration, topical administration, ophthalmic administration or otic administration. In some embodiments, the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop or an ear drop. In some embodiments, the composition further comprises one or more additional therapeutically active agents selected from 5-lipoxygenase-activating protein inhibitors, 5-lipoxygenase inhibitors, CYSLTR1 antagonists, CYSLTR2 antagonists, BLT1 antagonists, BLT2 antagonists, thromboxane antagonists, DP1 receptor antagonists, DP1 receptor agonists, IP receptor agonists, anti-IgE, chemokine receptor antagonists, IL5 antibody, bronchodilators, theophylline, leukotriene receptor antagonists, leukotriene formation inhibitors, decongestants, antihistamines, mucolytics, corticosteroids, glucocorticoids, anticholinergics, antitussives, analgesics, expectorants, and β-2 agonists. In some embodiments, the effective amount is an amount sufficient to ameliorate the symptoms of a PGD₂-dependent or PGD₂-mediated disease or condition in a subject in need thereof. In some embodiments, the subject is a human.

Also provided herein is a medicament for treating a PGD₂-dependent or PGD₂-mediated disease or condition in a subject comprising a therapeutically effective amount of a compound of any of Formulas (I), (II), or (III). In some embodiments, the subject is a human.

Also provided herein is the use of a compound of any of Formulas (I), (II), or (III) in the manufacture of a medicament for the treatment of a PGD₂-dependent or PGD₂-mediated disease or condition.

Also provided herein is a method for treating PGD₂-dependent or PGD₂-mediated disease or condition in a subject comprising administering to the subject a therapeutically effective amount of a compound of any of Formulas (I), (II), or (III). In some embodiments, the PGD₂-dependent or PGD₂-mediated disease or condition is selected from asthma, rhinitis, allergic conjuctivitis, atopic dermatitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, wound healing, endotoxic shock, pain, inflammatory conditions, eosinophilic esophagitis, eosinophil-associated gastrointestinal disorders (EGID), idiopathic hypereosinophilic syndrome, otitis, airway constriction, mucus secretion, nasal congestion, increased microvascular permeability and recruitment of eosinophils, urticaria, sinusitis, angioedema, anaphylaxia, chronic cough and Churg Strauss syndrome. In some embodiments, the PGD₂-dependent or PGD₂-mediated disease or condition is a respiratory disorder. In some embodiments, the respiratory disorder is asthma, rhinitis or chronic obstructive pulmonary disease (COPD). In some embodiments, the method further comprises administering to the subject a second therapeutic agent selected from 5-lipoxygenase-activating protein inhibitors, 5-lipoxygenase inhibitors, CYSLTR1 antagonists, CYSLTR2 antagonists, BLT1 antagonists, BLT2 antagonists, thromboxane antagonists, DP1 receptor antagonists, DP1 receptor agonists, IP receptor agonists, anti-IgE, chemokine receptor antagonists, ILS antibody, bronchodilators, theophylline, leukotriene receptor antagonists, leukotriene formation inhibitors, decongestants, antihistamines, mucolytics, corticosteroids, glucocorticoids, anticholinergics, antitussives, analgesics, expectorants, and β-2 agonists. In some embodiments, the subject is a human.

In some embodiments, compounds having the structure of Formula (I), (II), or (III) are used in treating a disease or condition mediated by prostaglandin D₂. In some embodiments, the disease or condition is a respiratory disease or condition, an allergic disease or condition, or an inflammatory disease or condition. In some embodiments, the disease or condition is a respiratory disease or condition or an allergic disease or condition. In some embodiments, the disease or condition is asthma, rhinitis or chronic obstructive pulmonary disease (COPD). In some embodiments, the disease or condition is asthma. In some embodiments, the disease or condition is rhinitis. In some embodiments, the disease or condition is chronic obstructive pulmonary disease (COPD).

In another aspect, compounds of Formula (I), (II), or (III) are used to treat or prevent immunological disorders, including, but are not limited to, allergy or to excessive or inappropriate response to an endogenous or exogenous antigen. In certain embodiments, the immunological disorder that is characterized by immune dysregulation that is not accompanied by inflammation.

In additional aspects, such diseases or conditions are iatrogenic and increases in, or abnormal localization of, PGD₂ is induced by other therapies or medical or surgical procedures. In other embodiments, the PGD₂-dependent or PGD₂ mediated condition or disease is caused by surgery.

In another aspect are methods for treating respiratory diseases or conditions in a mammal comprising administering to the mammal at least once an effective amount of at least one compound of Formula (I), (II), or (III). In a further embodiment of this aspect, the respiratory disease is asthma. In a further embodiment of this aspect, the respiratory disease includes, but is not limited to, asthma, adult respiratory distress syndrome, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, neutrophillic asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia.

In another aspect compounds described herein are used for treating rhinitis in a mammal. In a further embodiment of this aspect, compounds described herein are used for treating allergic (extrinsic) rhinitis, non-allergic (intrinsic) rhinitis, chronic rhinitis, allergen-induced rhinitis, aspirin-sensitive rhinitis, child-onset rhinitis, adult-onset rhinitis, occupational rhinitis, steroid-resistant rhinitis, seasonal rhinitis, perennial rhinitis, rhinosinusitis, and rhinopolyposis.

In another aspect are methods for treating chronic obstructive pulmonary disease comprising administering to the mammal at least once an effective amount of a compound of Formula (I), (II), or (III). In a further embodiment of this aspect, chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis and/or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis.

In another aspect are methods for preventing increased mucosal secretion and/or edema in mammals comprising administering to the mammal at least once an effective amount of a compound of Formula (I), (II), or (III).

In another aspect are methods for preventing eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte or Th2 cell recruitment comprising administering to the mammal an effective amount of a compound of Formula (I), (II), or (III).

In another aspect are methods for treating or preventing ocular inflammation, conjunctivitis, retinitis, scleritis, uveitis, allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis comprising administering to the mammal at least once an effective amount of a compound of Formula (I), (II), or (III).

In another aspect, compounds of Formula (I), (II), or (III) are used to treat or prevent pain.

In another aspect are methods for preventing or treating acute or chronic disorders involving recruitment or activation of eosinophils comprising administering to the mammal at least once an effective amount of a compound of Formula (I), (II), or (III).

In another aspect are methods for treating inflammatory responses of the skin comprising administering to the mammal at least once an effective amount of at least one compound of Formula (I), (II), or (III). Such inflammatory responses of the skin include, by way of example, psoriasis, dermatitis, atopic dermatitis, contact dermatitis, eczema, urticaria, rosacea, bullous disorders, collagenoses, Kawasaki Disease, Sjogren-Larsso Syndrome, wound healing and scarring. In another aspect are methods for reducing psoriatic lesions in the skin, joints, or other tissues or organs, comprising administering to the mammal an effective amount of a compound of Formula (I), (II), or (III). In another aspect are methods for reducing psoriatic lesions in the skin, joints, or other tissues or organs, comprising administering at least once to the mammal an effective amount of a compound of Formula (I), (II), or (III).

In a further aspect are methods to modulate the immune response to endogenous or exogenous antigens. In a further aspect are methods to treat acute or chronic allergic responses to exogenous substances that have been ingested such as foods (e.g., peanuts) or drugs (e.g., penicillin, non-steroidal anti-inflammatory drugs or the like).

In another aspect is the use of a compound of Formula (I), (II), or (III) in the manufacture of a medicament for treating an inflammatory disease or condition in a mammal in which the activity of at least one PGD₂-associated protein contributes to the pathology and/or symptoms of the disease or condition. In one embodiment of this aspect, the PGD₂ pathway protein is DP2. In another or further embodiment of this aspect, the inflammatory disease or conditions are respiratory, cardiovascular, or proliferative diseases.

In any of the aforementioned aspects are further embodiments in which: (a) the effective amount of the compound is systemically administered to the mammal; and/or (b) the effective amount of the compound is administered orally to the mammal; and/or (c) the effective amount of the compound is intravenously administered to the mammal; and/or (d) the effective amount of the compound administered by inhalation; and/or (e) the effective amount of the compound is administered by nasal administration; or and/or (I) the effective amount of the compound is administered by injection to the mammal; and/or (g) the effective amount of the compound is administered topically (dermal) to the mammal; and/or (h) the effective amount of the compound is administered by ophthalmic administration; and/or (i) the effective amount of the compound is administered rectally to the mammal.

In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once daily; (ii) the compound is administered twice daily; (iii) the compound is administered in cycles that include daily administration for a period of time followed by at least 1 day without administration; (iv) the compound is administered in cycles that include daily administration for a period of time followed by at least 1 day that includes a dose reduction in the daily amount of compound that is administered.

In any of the aforementioned aspects involving the treatment of PGD₂ dependent diseases or conditions are further embodiments comprising administering at least one additional agent in addition to the administartion of a compound having the structure of Formula (I).

In any of the aforementioned aspects involving the prevention or treatment of inflammation are further embodiments comprising: (a) monitoring inflammation in a mammal; (b) measuring bronchoconstriction in a mammal; (c) measuring eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte and/or lymphocyte recruitment in a mammal; (d) monitoring mucosal secretion in a mammal; (e) measuring mucosal edema in a mammal.

Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Prostaglandin D₂ (PGD₂) is an acidic lipid derived from the metabolism of arachidonic acid by cyclooxygenases and PGD₂ synthases. PGD₂ is produced by mast cells, macrophages and Th2 lymphocytes in response to local tissue damage as well as in response allergic inflammation observed in diseases such as asthma, rhinitis, and atopic dermatitis. More specifically, exogenous PGD₂ applied to bronchial airways elicits many responses that are characteristic of acute asthma.

PGD₂ is a major mast cell product that acts via two receptors, the D-type prostanoid (DP, also known as DP₁) and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2, also known as DP₂) receptors. DP₂ mediates the chemotaxis of eosinophils, basophils, and Th2 lymphocytes, and DP₁ receptor plays an important role in eosinophil trafficking. DP₁ antagonists do not inhibit the release of eosinophils when induced by the DP₂-selective agonists. However, eosinophils in human bone marrow specimens express DP₁ and DP₂ receptors at similar levels and human peripheral blood expresses both DP₁ and DP₂, but the DP₁ receptor is expressed at lower levels. In agreement with this, the chemotaxis of human peripheral blood eosinophils is inhibited by both DP₁ and DP₂ antagonists. Accordingly, DP₁, DP₂ and dual DP₁/DP₂ antagonists are useful in the treatment of allergic inflammation.

Activation of DP₂ is associated with chemotaxis and activation of Th2 lymphocytes, eosinophils and basophils. In particular, PGD₂ binds to DP₂ and mediates many of its effects through a G₁-dependent elevation of intracellular calcium levels and reduction of cyclic AMP. In Th2 lymphocytes, IL4, IL5 and IL13 cytokine production are also stimulated by DP₂ activation. These cytokines have been implicated in numerous biological actions including, by way of example only, immunoglobulin E production, airway response, mucous secretion, and eosinophil recruitment.

The terms CRTH2 and DP₂, refer to the same receptor and are used interchangeably herein. Likewise, another common name for DP is DP₁, and the two terms are used interchangeably herein.

Illustrative Biological Activity

Prostaglandins (PGs) are recognized physiological lipid acid mediators produced by the release of arachidonic acid from cell membrane phospholipids and converted to prostaglandins by the action of COX₁ and COX₂ cyclooxygenases and PG synthases. The cyclooxygenases sequentially convert arachidonic acid to cyclic endoperoxide prostaglandin G₂ (PGG₂) and subsequently, prostaglandin H₂ (PGH₂). Depending on the tissue, physiological signal, and/or synthase type, PGH₂ can be converted to numerous different prostaglandins, such as PGE₂, PGD₂, PGF₂α, and PGI₂ as well as thromboxane A₂, another eicosanoid signaling molecule. These mediators then elicit a wide variety of physiological responses including vasoconstriction or dilation, platelet aggregation, calcium transport, pain sensitization, hormone release, inflammatory and immune response, and cellular growth.

Prostaglandin D₂ is a major metabolite produced from the PGH₂ intermediate via hematopoietic PGD₂ synthase or lipocalin PGD₂ synthase. In the brain and central nervous system, PGD₂ is produced and thought to function in pain perception and sleep regulation. In other tissues, PGD₂ is produced primarily in immunoglobulin E (IgE) activated mast cells and to a lesser extent, in macrophages, dendritic cells, T helper 2 (Th2) lymphocytes and other leukocytes. In the cell, PGD₂ is rapidly metabolized and converted to other downstream effectors including Δ¹²PGJ₂, 9α11βPGF₂, 13,14-dihydro-15-keto-PGD₂, and 15-deoxy-Δ^(12,14)PGD₂.

Mast-cell-derived PGD₂ is produced in high concentrations in response to an allergen challenge. Studies in preclinical species have observed the following features when PGD₂ is applied to in vivo preparations, or its overproduction is engineered by genetic manipulation:

-   -   Vasodilatation leading to erythema (flare) and -potentiation of         oedema (wheal).     -   Recruitment of eosinophils and Th2 lymphocytes.     -   Modulation of Th2-cytokine production.     -   Bronchoconstriction.

Injection of PGD₂ into human skin has been shown to produce a long lasting erythema, to potentiate the effects of other mediators on induration and leukocyte infiltration in human skin and to enhance oedema formation in rat skin. It is most likely that these effects of PGD₂, like those of other vasodilator prostaglandins, are due to an increased blood flow to the inflamed lesion and are, therefore, most likely to be mediated predominantly by the DP₁ receptor. Although these observations make it clear that DP₁ mediates the vascular effects of PGD₂, the capacity of PGD₂ to promote the cellular changes associated with inflammation is not due to an action on DP₁.

The main receptors that are activated by PGD₂ or its metabolites and mediate its effects are DP₁, CRTH2 (or DP₂) and TP.

DP₁ (or DP) is a G-protein coupled seven-transmembrane receptor that, upon activation by PGD₂ binding, leads to an increase in intracellular cAMP levels. DP₁ is expressed in the brain, bronchial smooth muscle, vascular and airway smooth muscle, dendritic cells, and platelets and induces PGD₂ dependent bronchodilation, vasodilation, platelet aggregation inhibition, and suppression of cytokine production. Genetic analysis of DP₁ function using knock-out mice has shown that mice lacking DP do not develop asthmatic responses in an ovalbumin-induced asthma model. Analysis of selective DP antagonists in guinea pig allergic rhinitis models demonstrated dramatic inhibition of early nasal responses, as assessed by sneezing, mucosal plasma exudation and eosinophil infiltration. DP antagonism alleviates allergen-induced plasma exudation in the conjunctiva in a guinea pig allergic conjuctivitis model and antigen-induced eosinophil infiltration into the lung in a guinea pig asthma model.

Much of the pro-inflammatory activity of PGD₂ is through interaction with DP₂ (or CRTH2). DP₂ is a G-protein coupled receptor and is typically highly expressed in Th2 lymphocytes, eosinophils and basophils. DP₂ activation functions to directly activate and recruit Th2 lymphocytes and eosinophils. Activated Th2 lymphocytes produce and secrete inflammatory cytokines including IL4, IL5, and IL13. Despite binding PGD₂ with a similar affinity as DP₁, DP₂ is not structurally related to DP₁ and signals through a different mechanism—the effects of DP₂ are mediated through Gi-dependent elevation in intracellular calcium levels and reduction in intracellular levels of cyclic AMP. DP₂ activation is important in eosinophil recruitment in response to allergic challenge in such tissues as nasal mucosa, bronchial airways, and skin. The application of either PGD₂ or selective DP₂ agonists both exacerbate and enhance allergic responses in lung and skin. DP₂ activation appears to have a crucial role in mediating allergic responses, and thus the use of antagonists of PGD₂ activation of the DP₂ receptor are an attractive approach to treat the inflammatory component of allergic diseases such as asthma, rhinitis, and dermatitis.

TP receptors primarily function to antagonize DP₁ receptor's effects such as promoting bronchoconstriction, vasoconstriction, and platelet aggregation. While TP receptor's main ligand is thromboxane A₂, it also binds and is activated by the PGD₂ derivative, 9α11βPGF₂. TP is a Gq-coupled prostanoid receptor that binds thromboxane with high affinity, promoting platelet aggregation and constriction of both vascular and airway smooth muscle. PGD₂ activates the TP receptor in human bronchial muscle, probably through the formation of the 11-ketoreductase metabolite 9α11βPGF2. The bronchoconstrictor effects of TP dominate over the bronchodilator effects of DP₁ in the airways.

DP₁ and DP₂ have crucial, and complementary, roles in the physiological response of animals to PGD₂ and blockade of either one or both of these receptors may prove beneficial in alleviating allergic diseases or conditions triggered by PGD₂, such as, but not limited to, allergic rhinitis, asthma, dermatitis, and allergic conjunctivitis.

Presented herein are compounds, pharmaceutical compositions and medicaments, methods, for (a) diagnosing, preventing, or treating allergic and non-allergic inflammation, (b) mitigating adverse signs and symptoms that are associated with inflammation, and/or (c) controlling immunological, proliferative or metabolic disorders. These disorders may arise from one or more of a genetic, iatrogenic, immunological, infectious, metabolic, oncological, toxic, surgical, and/or traumatic etiology. In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein comprise antagonists of PGD₂ receptors. In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein comprise antagonists of DP₂.

In some embodiments provided herein are compounds of Formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, which are antagonists of DP₂, and are used to treat subjects suffering from one or more PGD₂-dependent conditions or diseases, including, but not limited to, asthma, rhinitis, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory conditions. In some embodiments, PGD₂-dependent conditions or diseases include those wherein an absolute or relative excess of PGD₂ is present and/or observed.

Compounds

Compounds of any of Formula (I), Formula (II), or Formula (III) including pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, antagonize or modulate DP₂ and are used to treat subjects suffering from PGD₂-dependent or PGD₂ mediated conditions or diseases, including, but not limited to, asthma, rhinitis, dermatitis, and inflammatory conditions.

In some embodiments provided herein is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

wherein,

R¹, R², R³, and R⁴ each are independently selected from H, halogen, —CN, —NO₂, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —C(═O)R¹², —OC(═O)R¹², —CO₂R¹³, —OCO₂R¹², —N(R¹³)₂, —C(═O)N(R¹³)₂, —OC(═O)N(R¹³)₂, —NHC(═O)R¹², —NHC(═O)OR¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, optionally substituted phenyl, and an optionally substituted monocyclic heteroaryl;

-   -   R⁵ is L⁵-X⁵;         -   L⁵ is —C₁-C₆alkyl-, —C₁-C₆flouroalkyl-, or             —C₃-C₆cycloalkyl-, an optionally substituted             —C₁-C₆alkyl-aryl, an optionally substituted             —C₁-C₆alkyl-heteroaryl, an an optionally substituted aryl,             or an optionally substituted heteroaryl;         -   X⁵ is a polar substituent;     -   R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, an         optionally substituted cycloalkyl, an optionally substituted         heterocycloalkyl, an optionally substituted aryl, an optionally         substituted heteroaryl, an optionally substituted         —C₁-C₆alkyl-cycloalkyl, an optionally substituted         —C₁-C₆alkyl-heterocycloalkyl, an optionally substituted         —C₁-C₆alkyl-aryl, or an optionally substituted         —C₁-C₆alkyl-heteroaryl;     -   R⁷ is L⁷-X⁷;         -   L⁷ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, or an optionally             substituted C₃-C₆cycloalkyl;         -   X⁷ is —CO₂H, —CO₂R¹², —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂,             —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹²,             —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹²,             —OH, —OR¹², —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂,             —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or             —C(═NR¹⁴)N(R¹³)₂;     -   each R⁸ and R⁹ is independently selected from H, C₁-C₄alkyl, and         C₁-C₄haloalkyl;     -   two R⁸ groups are taken together with the carbon atom to which         they are attached to form a carbonyl (—C(═O)—);

both R⁹ groups are taken together with the carbon atom to which they are attached to form a carbonyl (—C(═O)—);

-   -   R¹⁰ is H, C₁-C₄alkyl, C₁-C₄haloalkyl, or -L¹⁰-X¹⁰;         -   L¹⁰- is —C₁-C₆alkyl-, or —C₃-C₆cycloalkyl-, an optionally             substituted —C₁-C₆alkyl-aryl or an optionally substituted             —C₁-C₆alkyl-heteroaryl;         -   X¹⁰ is —CO₂R¹³, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH,             —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂,             —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OR¹³, —SR¹²,             —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹²,             —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂;     -   R¹² is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl,         optionally substituted cycloalkyl, optionally substituted         heterocycloalkyl, optionally substituted aryl, optionally         substituted benzyl or optionally substituted heteroaryl;     -   each R¹³ is independently selected from H, C₁-C₆alkyl,         C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, an optionally substituted         cycloalkyl, an optionally substituted heterocycloalkyl, an         optionally substituted aryl, an optionally substituted benzyl,         and an optionally substituted heteroaryl;     -   two R¹³ groups attached to the same N atom are taken together         with the N atom to which they are attached to form an optionally         substituted heterocycloalkyl;     -   R¹⁴ is selected from among H, —S(═O)₂R¹², —S(═O)₂NH₂, —C(═O)R¹²,         —CN, and —NO₂;     -   m is 1, 2, or 3.

For any and all of the embodiments, substituents can be selected from among from a subset of the listed alternatives. For example, in some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OH, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OH, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —SR¹², —S(═O)R¹², —S(═O)₂R¹², or —N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, or —N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —S(═O)₂N(R¹³)₂, or —OH.

In some embodiments, each R⁸ and R⁹ is each independently selected from H, or —CH₃; or two R⁸ groups are taken together with the carbon atom to which they are attached to form a carbonyl(-C(═O)—); or both R⁹ groups are taken together with the carbon atom to which they are attached to form a carbonyl(-C(═O)—); and m is 1 or 2.

In some embodiments, R¹, R², R³, and R⁴ each are independently selected from H, halogen, —CN, —NO₂, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —C(═O)R¹², —OC(═O)R¹², —CO₂R¹³, —OCO₂R¹², —N(R¹³)₂, —C(═O)N(R¹³)₂, —OC(═O)N(R¹³)₂, —NHC(═O)R¹², —NHC(═O)OR¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, optionally substituted phenyl, and an optionally substituted monocyclic heteroaryl, provided that at least two of R¹, R², R³, and R⁴ are H.

In some embodiments, R¹, R², R³, and R⁴ each are independently selected from H, halogen, —CN, —OH, —OR¹³, —S(═O)₂C₁-C₆alkyl, —S(═O)₂N(R¹³)₂, —NHS(═O)₂R¹², —OC(═O)R¹², —C(═O)N(R¹³)₂, —NHC(═O)R¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl. In some embodiments, R¹, R², R³, and R⁴ each are independently selected from H, halogen, —CN, —OH, —OR¹³, —S(═O)₂C₁-C₆alkyl, —S(═O)₂N(R¹³)₂, —NHS(═O)₂R¹², —OC(═O)R¹², —C(═O)N(R¹³)₂, —NHC(═O)R¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl, provided that at least two of R¹, R², R³, and R⁴ are H.

In some embodiments, R⁶ is C₁-C₆alkyl, C₁-C₆ fluoroalkyl, C₁-C₆heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted heteroaryl containing 0-3 N atoms, an optionally substituted —C₁-C₆alkyl-cycloalkyl, an optionally substituted —C₁-C₆alkyl-heterocycloalkyl, an optionally substituted —C₁-C₆alkyl-phenyl, or an optionally substituted —C₁-C₆alkyl-heteroaryl.

In some embodiments, L⁷ is C₁-C₆alkyl, C₁-C₆ fluoroalkyl, or an optionally substituted C₃-C₆cycloalkyl; X⁷ is —CO₂R¹³, —C(═O)N(R¹³)₂, tetrazolyl, —OH, or —C(═O)NHC(═O)R¹². In some embodiments, L¹ is C₁-C₆alkyl.

In some embodiments, L⁵ is —C₁-C₆alkyl, or an optionally substituted —C₁-C₆alkyl-phenyl; and X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —OR¹³, —S(═O)R¹², —S(═O)₂R¹², or —N(R¹³)₂. In some embodiments, L⁵ is —C₁-C₆alkyl.

In some embodiments, R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, an optionally substituted C₃-C₁₀cycloalkyl, an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl containing 0-3 N atoms, an optionally substituted —C₁-C₆alkyl-cycloalkyl, an optionally substituted —C₁-C₆alkyl-phenyl, or an optionally substituted —C₁-C₆alkyl-(monocyclic heteroaryl).

In some embodiments, L⁵ is C₁-C₆alkyl; X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —OR¹³, —SR¹², —S(═O)₂, or —N(R¹³)₂. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —S(═O)₂R¹², or —N(R¹³)₂.

In some sembodiments, L⁷ is C₁-C₆alkyl; X⁷ is CO₂H, —CO₂(C₁-C₆alkyl), or —OH. In some sembodiments, X⁷ is CO₂H, or —OH.

In some embodiments, R¹⁰ is H or C₁-C₄alkyl.

In some embodiments, each of R⁸ and R⁹ is H.

In some embodiments, the compound of Formula (I) has the following structure:

In some embodiments, m is 1.

In some embodiments, the compound of Formula (I) has the structure of Formula (II):

In some embodiments, m is 2.

In some embodiments, the compound of Formula (I) has the structure of Formula (III):

In some embodiments, R¹⁰ is H or —CH₃. In some embodiments, R¹⁰ is H.

In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, —OH, or —OR¹³. In some embodiments, X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, or —OH.

In some embodiments, R¹, R², R³, and R⁴ each are independently selected from H, F, Cl, Br, I, —CN, —OH, —OCH₃, —S(═O)₂CH₃, —CH₃, and —CF₃; and R¹⁰ is H. In some embodiments, R¹, R², R³, and R⁴ each are independently selected from H, F, Cl, Br, I, —CN, —OH, —OCH₃, —S(═O)₂CH₃, —CH₃, and —CF₃, provided that at least two of R¹, R², R³, and R⁴ are H. In some embodiments, each of R¹, R², R³, and R⁴ are H.

In some embodiments, R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted monocyclic heteroaryl containing 0-3 N atoms. In some embodiments, R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, or an optionally substituted phenyl. In some embodiments, R⁶ is an optionally substituted phenyl.

In some embodiments, R⁷ is —CH₂CO₂H, —CH₂CH₂CO₂H, —C(CH₃)₂OH, —CH₂C(CH₃)₂OH, or —CH₂CH₂C(CH₃)₂OH.

In some embodiments, R⁵ is —CH₂CO₂H, —CH₂C(CH₃)₂OH, or —CH₂C(═O)NH₂.

Any combination of the groups described above for the various variables is contemplated herein.

In some embodiments, the compounds of any of Formula (I), Formula (II), or Formula (III), include, but are not limited to:

Compound No. R⁷ R⁵ R⁶ 1-1 —CH₂CO₂H —CH₂CO₂H 4-fluorophenyl 1-2 —CH₂CH₂C(CH₃)₂OH —CH₂CO₂H 4-fluorophenyl 1-3 —CH₂CH₂CO₂H —CH₂C(CH₃)₂OH 4-fluorophenyl 1-4 —CH₂CH₂C(CH₃)₂OH —CH₂C(CH₃)₂OH 4-fluorophenyl 1-5 —CH₂CH₂CO₂H —CH₂C(═O)NH₂ 4-fluorophenyl 1-6 —CH₂CH₂CO₂H —CH₂CO₂H 4-fluorophenyl

Synthesis of Compounds

Compounds of Formula (I), Formula (II), and Formula (III) described in the prior section are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. In additions, solvents, temperatures and other reaction conditions presented herein may vary.

The starting material used for the synthesis of the compounds of Formula (I), Formula (II), and Formula (III) described in the prior section are either synthesized or obtained from commercial sources, such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.), or Sigma Chemical Co. (St. Louis, Mo.). The compounds described herein, and other related compounds having different substituents are synthesized using known techniques and materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd) Ed., (Wiley 1999). General methods for the preparation of compounds can be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formulae as provided herein.

In one aspect, compounds of Formula (I) have the structure of Formula 1-IV. In one aspect, compounds of general structure 1-IV are prepared as outlined in Scheme 1.

Amine 1-I (Rosentreter et al, Arzneim.-Forsch./Drug Res., 1989, 39, p 1519; in racemic, (+)- or (−)-form) is reacted with a sulfonyl chloride in the presence of a base and a solvent to produce 1-II. In one aspect the base is Et₃N. In one aspect, the solvent is an organic solvent (e.g. THF). Deprotonation of the indole N—H of 1-II using a strong base and subsequent alkylation with an electrophile R⁷—X yields 1-III. A second alkylation using R⁵—X then allows for N-alkylation of the sulfonamide to give 1-IV. Treatment of 1-II with an excess of strong base followed by double alkylation will provide 1-IV in which R⁵ and R⁷ are the same.

In one aspect, indoles of structure 1-II are alkylated as shown in Scheme 2.

Indoles of structure 1-II are N-alkylated using NaH and acrylonitrile in THF (Rosentreter et al, Arzneim.-Forsch./Drug Res., 1989, 39, p 1519; Scheme 2) to provide compounds of structure 2-II. Hydrolysis of the nitrile then affords 2-II. Treatment of 2-H with excess base, such as NaH, in a solvent, such as DMF, followed by alkylation of the sulfonamide then yields the bis-alkylated product 2-III. Aqueous hydrolysis of compounds of structure 2-III then provides compounds of structure 2-IV.

In one aspect, compounds of structure 2-III are derivatized as outlined in Scheme 3.

Compounds of structure 2-III (Scheme 3; R⁵ is —CH₂CO₂Me) are further derivatized by reaction with a Grignard reagent or alkyl lithium reagent in a solvent such as THF. Subsequent treatment with aqueous base (e.g. LiOH) of the crude product and separation using standard methodologies such as HPLC allows for the preparation of compounds 3-II, 3-III, and 3-IV.

In one aspect, compounds of structure 2-II are further derivatived as outlined in Scheme 4.

Reaction of compounds of structure 2-II with R⁵-X provides compounds of structure 4-I. In one aspect, R⁵—X is bromo acetonitrile. Reaction of compounds of structure 4-I (R⁵ is —CH₂CN) with concentrated HCl in a solvent such as methanol followed by base hydrolysis to yield the amides of structure 4-II.

In one aspect, the compound of Formula (I) has a structure of Formula 1-IV. In one aspect, the compound of Formula (I) has a structure of Formula 2-III. In one aspect, the compound of Formula (I) has a structure of Formula 2-IV. In one aspect, the compound of Formula (I) has a structure of Formula 3-II. In one aspect, the compound of Formula (I) has a structure of Formula 3-III. In one aspect, the compound of Formula (I) has a structure of Formula 4-I. In one aspect, the compound of Formula (I) has a structure of Formula 4-II.

Formation of Covalent Linkages by Reaction of an Electrophile with a Nucleophile

In certain embodiments, the compounds described herein are modified using various electrophiles or nucleophiles to form new functional groups or substituents. Table 1 entitled “Examples of Covalent Linkages and Precursors Thereof” lists selected, non-limiting examples of covalent linkages and precursor functional groups that are used to prepare the modified compounds. Precursor functional groups are shown as electrophilic groups and nucleophilic groups.

TABLE 1 Examples of Covalent Linkages and Precursors Thereof Covalent Linkage Product Electrophile Nucleophile Carboxamides Activated esters amines/anilines Carboxamides acyl azides amines/anilines Carboxamides acyl halides amines/anilines Esters acyl halides alcohols/phenols Esters acyl nitriles alcohols/phenols Carboxamides acyl nitriles amines/anilines Imines Aldehydes amines/anilines Hydrazones aldehydes or ketones Hydrazines Oximes aldehydes or ketones Hydroxylamines Alkyl amines alkyl halides amines/anilines Esters alkyl halides carboxylic acids Thioethers alkyl halides Thiols Ethers alkyl halides alcohols/phenols Thioethers alkyl sulfonates Thiols Esters alkyl sulfonates carboxylic acids Ethers alkyl sulfonates alcohols/phenols Esters Anhydrides alcohols/phenols Carboxamides Anhydrides amines/anilines Thiophenols aryl halides Thiols Aryl amines aryl halides Amines Thioethers Azindines Thiols Boronate esters Boronates Glycols Carboxamides carboxylic acids amines/anilines Esters carboxylic acids Alcohols hydrazines Hydrazides carboxylic acids N-acylureas or Anhydrides carbodiimides carboxylic acids Esters diazoalkanes carboxylic acids Thioethers Epoxides Thiols Thioethers haloacetamides Thiols Ammotriazines halotriazines amines/anilines Triazinyl ethers halotriazines alcohols/phenols Amidines imido esters amines/anilines Ureas Isocyanates amines/anilines Urethanes Isocyanates alcohols/phenols Thioureas isothiocyanates amines/anilines Thioethers Maleimides Thiols Phosphite esters phosphoramidites Alcohols Silyl ethers silyl halides Alcohols Alkyl amines sulfonate esters amines/anilines Thioethers sulfonate esters Thiols Esters sulfonate esters carboxylic acids Ethers sulfonate esters Alcohols Sulfonamides sulfonyl halides amines/anilines Sulfonate esters sulfonyl halides phenols/alcohols

Use of Protecting Groups

In the reactions described, it is necessary in certain embodiments to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Protecting groups are used to block some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In one embodiment, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. In some embodiments, protective groups are removed by acid, base, and/or hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used in certain embodiments to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and/or Fmoc groups, which are base labile. In other embodiments, carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.

In another embodiment, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. In another embodiment, carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, or they are, in yet another embodiment, blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups are blocked with fluoride labile silyl carbamates.

Allyl blocking groups are useful in the presence of acid- and base-protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pd(0)-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.

Typically blocking/protecting groups are, by way of example only:

Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, N.Y., 1994, which are incorporated herein by reference for such disclosure.

In certain embodiments, compounds are prepared using standard procedures such as those found in Katritzky, “Handbook of Heterocyclic Chemistry” Pergamon Press, Oxford, 1986; Pindur et al, J. Heterocyclic Chem., vol 25, 1, 1987, and Robinson “The Fisher Indole Synthesis”, John Wiley & Sons, Chichester, New York, 1982, are incorporated herein by reference for such disclosure.

Further Forms of Compounds

In certain embodiments, compounds of any of Formula (I), Formula (II), or Formula (III), are prepared as a pharmaceutically acceptable acid addition salt (which is a type of a pharmaceutically acceptable salt) by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

By “pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of any of Formula (I), Formula (II), or Formula (III), with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutically acceptable salts are also obtained by reacting a compound of any of Formula (I), Formula (II), or Formula (III), with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.

In other embodiments, compounds of any of Formula (I), Formula (II), or Formula (III), are prepared as a pharmaceutically acceptable salts by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base, including, but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like, or with an inorganic base such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are optionally formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds of any of Formula (I), Formula (II), or Formula (III), are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of compounds of any of Formula (I), Formula (II), or Formula (III), are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, ethanol, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

In yet other embodiments, the compounds of any of Formula (I), Formula (II), or Formula (III), are prepared in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate forms. In addition, compounds of any of Formula (I), Formula (II), or Formula (III), include crystalline forms, also known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

In some embodiments, compounds of any of Formula (I), Formula (II), or Formula (III), are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of any of Formula (I), Formula (II), or Formula (III), which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.

Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. In certain embodiments, the prodrug of a compound described herein is bioavailable by oral administration whereas the parent is not. Furthermore, in some embodiments, the prodrug of a compound described herein has improved solubility in pharmaceutical compositions over the parent drug.

In other embodiments, prodrugs are designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. In specific embodiments, the design of prodrugs to date is to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent. Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

Additionally, prodrug derivatives of compounds of any of Formula (I), Formula (II), or Formula (III), are prepared, if desired (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). By way of example only, in one aspect appropriate prodrugs are prepared by reacting a non-derivatized compound of any of Formula (I), Formula (II), or Formula (III), with a suitable carbamylating agent, such as, but not limited to, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like. Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. Indeed, some of the herein-described compounds are a prodrug for another derivative or active compound.

In some embodiments, sites on the aromatic ring portion of compounds of any of Formula (I), Formula (II), or Formula (III), are susceptible to various metabolic reactions Therefore incorporation of appropriate substituents on the aromatic ring structures will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group.

In another embodiment, the compounds described herein are labeled isotopically or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. In some embodiments, compounds described herein are isotopically-labeled, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. In some embodiments, one or more hydrogen atoms are replaced with deuterium. In some embodiments, metabolic sites on the compounds described herein are deuterated. In some embodiments, substitution with deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

In yet another embodiment, the compounds of any of Formula (I), Formula (II), or Formula (III), possess one or more stereocenters and each center exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. In certain embodiments, compounds of any of Formula (I), Formula (II), or Formula (III), are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In other embodiments, dissociable complexes are utilized (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are, in specific embodiments, separated by taking advantage of these dissimilarities. In these embodiments, the diastereomers are separated by chiral chromatography or by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981.

Additionally, in certain embodiments, the compounds provided herein exist as geometric isomers. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. In some embodiments, the compounds described herein exist as tautomers. All tautomers are intended to be within the scope of the molecular formulas described herein. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are envisioned.

Certain Chemical Terminology

Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. In this application, the use of “or” or “and” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as defined herein.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl moiety may be a saturated alkyl group, which means that it does not contain any units of unsaturation (e.g. carbon-carbon double bonds or carbon-carbon triple bonds). The alkyl moiety may also be an unsaturated alkyl moiety, which means that it contains at least one unit of unsaturation. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic. The point of attachment of an alkyl is at a carbon atom that is not part of a ring.

The “alkyl” moiety has between 1 to 10 carbon atoms (whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the compounds described herein may be designated as “C₁-C₄ alkyl” or similar designations. By way of example only, “C₁-C₄ alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, hexyl, allyl, but-2-enyl, but-3-enyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. In one aspect, an alkyl is a C₁-C₆ alkyl.

An “amide” is a chemical moiety with formula —C(═O)NHR or —NHC(═O)R, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). An amide may be an amino acid or a peptide molecule attached to a compound of Formula (I), Formula (II), or Formula (III) thereby forming a prodrug. Any amine, or carboxyl side chain on the compounds described herein is optionally amidified, as desired. See, e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999, is incorporated herein by reference for such disclosure.

The term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, ten, or more than ten atoms. Aromatics are optionally substituted. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

The term “carbocyclic” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon.

As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings are formed by five, six, seven, eight, nine, or more than nine carbon atoms. In one aspect, an aryl is a C₆-C₁₀aryl. Aryl groups are optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. In some embodiments, an awl is a phenyl. Depending on the structure, an awl group can be a monoradical or a diradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:

and the like. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, bicyclic cycloalkyl groups are selected from among indanyl, indenyl, and 1,2,3,4-tetrahydronaphthalenyl. Cycloalkyl groups may be substituted or unsubstituted. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (i.e., an cycloalkylene group, such as, but not limited to, cyclopropan-1,1-diyl, cyclobutan-1,1-diyl, cyclopentan-1,1-diyl, cyclohexan-1,1-diyl, cycloheptan-1,1-diyl, and the like).

The term “ester” refers to a chemical moiety with formula —COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). Any hydroxy, or carboxyl side chain on the compounds described herein is esterified, if desired. Examples of procedures and specific groups to make such esters are found in sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo.

The term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halide atoms. In one aspect, a haloalkyl is a C₁-C₆haloalkyl.

The term “fluoroalkyl” refers to a alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is a C₁-C₆fluoroalkyl. Examples of fluoroalkyls include, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃ and —CF₂CF₃.

The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. In one aspect, a heteroalkyl is a C₁-C₆ heteroalkyl. In some embodiments, heteroalkyl refers to an alkyl group in which one of the skeletal atoms of the alkyl is oxygen or nitrogen.

The term “heterocycle” refers to heteroaromatic and heteroalicyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 3-membered heterocyclic group is aziridinyl. An example of a 4-membered heterocyclic group is azetidinyl. An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, futyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles may be substituted with one or two oxo (═O) moieties, such as pyrrolidin-2-one.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include the following moieties:

and the like. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. In one aspect, the heteroaryl is a C₁-C₁₀heteroaryl. In another aspect, the heteroaryl is a C₂-C₉heteroaryl. In some cases, the heteroaryl includes at least one N atom in the ring. In one aspect, monocyclic heteroaryl is a C₁-C₅heteroaryl. In one aspect, bicyclic heteroaryl is a C₅-C₁₀heteroaryl.

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include:

and the like. In some embodiments, the heterocycloalkyl is selected from oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and indolinyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is a C₄-C₁₀heterocycloalkyl.

The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.

The term “membered ring” includes any cyclic structure. The term “membered” is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, cyclohexyl, pyridinyl, pyranyl and thiopyranyl are 6-membered rings and cyclopentyl, pyrrolyl, furanyl, and thiophenyl are 5-membered rings.

The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, carbonyl, thiocarbonyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. By way of example an optional substituents may be halide, —CN, —NO₂, or L_(s)R_(s), wherein each L_(s) is independently selected from a bond, —O—, —C(═O)—, —C(═O)O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(═O)—, —C(═O)NH—, S(═O)₂NH—, —NHS(═O)₂, —OC(═O)NH—, —NHC(═O)O—, —(C₁-C₆ alkyl), or —(C₂-C₆ alkenyl); and each R_(s) is independently selected from H, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. The protecting groups that may form the protective derivatives of the above substituents may be found in sources such as Greene and Wuts, above. In some embodiments, optional substituents are selected from halogen, —CN, —NH₂, —OH, —N(CH₃)₂, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, —S-alkyl, —S-aryl, —S(═O)-alkyl, —S(═O)-aryl, —S(═O)₂-alkyl, and —S(═O)₂-aryl. In some embodiments, an optional substituents is F, Cl, Br, I, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, or —SO₂alkyl. In some embodiments, substituted groups are substituted with one or more substituents selected from F, Cl, Br, —OH, —OCH₃, —CH₃, and —CF₃. In some embodiments, substituted groups are substituted with one of the preceding groups.

In certain embodiments, the compounds presented herein possess one or more stereocenters and each center independently exists in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers are obtained, if desired, by methods such as, the separation of stereoisomers by chiral chromatographic columns.

The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, or pharmaceutically acceptable salts of compounds having the structure of any of Formula (I), Formula (II), or Formula (III) as well as active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In specific embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated form.

Certain Pharmaceutical and Medical Terminology

The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

The term “modulate,” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

The term “modulator,” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist and antagonist. In one embodiment, a modulator is an antagonist.

The term “agonist,” as used herein, refers to a molecule such as a compound, a drug, an enzyme activator or a hormone modulator that binds to a specific receptor and triggers a response in the cell. An agonist mimics the action of an endogenous ligand (such as prostaglandin, hormone or neurotransmitter) that binds to the same receptor.

The term “antagonist,” as used herein, refers to a molecule such as a compound, which diminishes, inhibits, or prevents the action of another molecule or the activity of a receptor site. Antagonists include, but are not limited to, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, partial agonists and inverse agonists.

Competitive antagonists reversibly bind to receptors at the same binding site (active site) as the endogenous ligand or agonist, but without activating the receptor.

Non-competitive antagonists (also known as allosteric antagonists) bind to a distinctly separate binding site from the agonist, exerting their action to that receptor via the other binding site. Non-competitive antagonists do not compete with agonists for binding. The bound antagonists may result in a decreased affinity of an agonist for that receptor, or alternatively may prevent conformational changes in the receptor required for receptor activation after the agonist binds.

Uncompetitive antagonists differ from non-competitive antagonists in that they require receptor activation by an agonist before they can bind to a separate allosteric binding site.

Partial agonists are defined as drugs which, at a given receptor, might differ in the amplitude of the functional response that they elicit after maximal receptor occupancy. Although they are agonists, partial agonists can act as a competitive antagonist if co-administered with a full agonist, as it competes with the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with the full agonist alone.

An inverse agonist can have effects similar to an antagonist, but causes a distinct set of downstream biological responses. Constitutively active receptors which exhibit intrinsic or basal activity can have inverse agonists, which not only block the effects of binding agonists like a classical antagonist, but inhibit the basal activity of the receptor.

The term “PGD₂-dependent”, as used herein, refers to conditions or disorders that would not occur, or would not occur to the same extent, in the absence of PGD₂.

The term “PGD₂-mediated”, as used herein, refers to refers to conditions or disorders that might occur in the absence of PGD₂ but can occur in the presence of PGD₂.

The term “asthma” as used herein refers to any disorder of the lungs characterized by variations in pulmonary gas flow associated with airway constriction of whatever cause (intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma may be used with one or more adjectives to indicate cause.

The term “rhinitis” as used herein refers to any disorder of the nose in which there is inflammation of the mucous lining of the nose by whatever cause (intrinsic, extrinsic or both; allergic or non-allergic).

The term “bone disease,” as used herein, refers to a disease or condition of the bone, including, but not limited to, inappropriate bone remodeling, loss or gain, osteopenia, osteomalacia, osteofibrosis, and Paget's disease.

The term “cardiovascular disease,” as used herein refers to diseases affecting the heart or blood vessels or both, including but not limited to: arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue.

The term “cancer,” as used herein refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). The types of cancer include, but is not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma) or hematological tumors (such as the leukemias).

The term “carrier,” as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.

The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

The term “dermatological disorder,” as used herein refers to a skin disorder. Such dermatological disorders include, but are not limited to, proliferative or inflammatory disorders of the skin such as, atopic dermatitis, bullous disorders, collagenoses, contact dermatitis eczema, Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, urticaria.

The term “diluent” refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution.

The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

The terms “fibrosis” or “fibrosing disorder,” as used herein, refers to conditions that follow acute or chronic inflammation and are associated with the abnormal accumulation of cells and/or collagen and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, joints, lung, or skin, and includes such disorders as idiopathic pulmonary fibrosis and cryptogenic fibrosing alveolitis.

The term “iatrogenic” means a PGD₂-dependent or PGD₂-mediated condition, disorder, or disease created or worsened by medical or surgical therapy.

The term “inflammatory disorders” refers to those diseases or conditions that are characterized by one or more of the signs of pain, heat, redness, swelling, and loss of function (temporary or permanent). Inflammation takes many forms and includes, but is not limited to, inflammation that is one or more of the following: acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and/or ulcerative. Inflammatory disorders further include, without being limited to those affecting the blood vessels (polyarteritis, temporal arteritis); joints (arthritis: crystalline, osteo-, psoriatic, reactive, rheumatoid, Reiter's); gastrointestinal tract (colitis); skin (dermatitis); or multiple organs and tissues (systemic lupus erythematosus).

The term “immunological disorders” refers to those diseases or conditions that are characterized by inappropriate or deleterious response to an endogenous or exogenous antigen that may result in cellular dysfunction or destruction and consequently dysfunction or destruction of an organ or tissue and which may or may not be accompanied by signs or symptoms of inflammation.

The terms “kit” and “article of manufacture” are used as synonyms.

A “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.

The terms “neurodegenerative disease” or “nervous system disorder,” as used herein, refers to conditions that alter the structure or function of the brain, spinal cord or peripheral nervous system, including but not limited to Alzheimer's Disease, cerebral edema, cerebral ischemia, multiple sclerosis, neuropathies, Parkinson's Disease, those found after blunt or surgical trauma (including post-surgical cognitive dysfunction and spinal cord or brain stem injury), as well as the neurological aspects of disorders such as degenerative disk disease and sciatica. The acronym “CNS” refers to disorders of the central nervous system, i.e., brain and spinal cord.

The terms “ocular disease” or “ophthalmic disease,” as used herein, refer to diseases which affect the eye or eyes and potentially the surrounding tissues as well. Ocular or ophthalmic diseases include, but are not limited to, conjunctivitis, retinitis, scleritis, uveitis, allergic conjunctivitis, vernal conjunctivitis, papillary conjunctivitis.

The term “interstitial cystitis” refers to a disorder characterized by lower abdominal discomfort, frequent and sometimes painful urination that is not caused by anatomical abnormalities, infection, toxins, trauma or tumors.

The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound of any of Formula (I), Formula (II), or Formula (III) and a co-agent, are both administered to a subject simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound of any of Formula (I), Formula (II), or Formula (III) and a co-agent, are administered to a subject as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the subject. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

The term “pharmaceutical composition” refers to a mixture of a compound of any of Formula (I), Formula (II), or Formula (III) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.

The term “respiratory disease,” as used herein, refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, Eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphragm and intercostals) and nerves. Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, neutrophilic asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia.

The term “subject” or “subject” encompasses mammals, including but not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically.

Pharmaceutical Composition/Formulation

In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound of any of Formula (I), Formula (II), or Formula (III) and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which compounds of any of Formula (I), Formula (II), or Formula (III) are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more compounds of any of Formula (I), Formula (II), or Formula (III).

A pharmaceutical composition, as used herein, refers to a mixture of a compound of any of Formula (I), Formula (II), or Formula (III) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds of any of Formula (I), Formula (II), or Formula (III) provided herein are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

In one embodiment, one or more compounds of any of Formula (I), Formula (II), or Formula (III) is formulated in an aqueous solutions. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compound of any of Formula (I), Formula (II), or Formula (III) is formulated for transmucosal administration. In specific embodiments, transmucosal formulations include mucoadhesive agents that provide for association between the formulation and a mucosal membrane, and/or penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients.

In another embodiment, compounds described herein are formulated for oral administration. Compounds described herein, including compounds of any of Formula (I), Formula (II), or Formula (III) are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.

In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses.

In certain embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

In other embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels.

In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical composition of any of Formula (I), Formula (II), or Formula (III) are formulated in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, suspensions of the active compounds are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

In one aspect, compounds of Formula (I), Formula (II), or Formula (III) are prepared as solutions for parenteral injection as described above and administered with an automatic injector. Automatic injectors, such as those disclosed in U.S. Pat. Nos. 4,031,893, 5,358,489; 5,540,664; 5,665,071, 5,695,472 and WO/2005/087297 (each of which are incorporated herein by reference in its entirety) are known. In general, all automatic injectors contain a volume of solution that includes a compound of Formula (I), Formula (II), or Formula (III) to be injected. In general, automatic injectors include a reservoir for holding the solution, which is in fluid communication with a needle for delivering the drug, as well as a mechanism for automatically deploying the needle, inserting the needle into the patient and delivering the dose into the patient. Exemplary injectors provide about 0.3 mL of solution at about a concentration of 0.5 mg to 10 mg of compound of Formula (I), Formula (II), or Formula (III) per 1 mL of solution. Each injector is capable of delivering only one dose of the compound.

In still other embodiments, the compounds of any of Formula (I), Formula (II), or Formula (III) are administered topically. The compounds described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

In yet other embodiments, the compounds of any of Formula (I), Formula (II), or Formula (III) are formulated for transdermal administration. In specific embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the compounds of any of Formula (I), Formula (II), or Formula (III) is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the compounds of any of Formula (I), Formula (II), or Formula (III). In specific embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

In other embodiments, the compounds of any of Formula (I), Formula (II), or Formula (III) are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders. Pharmaceutical compositions of any of Formula (I), Formula (II), or Formula (III) are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

In still other embodiments, the compounds of any of Formula (I), Formula (II), or Formula (III) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients is optionally used as suitable and as understood in the art. Pharmaceutical compositions comprising a compound of any of Formula (I), Formula (II), or Formula (III) may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and at least one compound of any of Formula (I), Formula (II), or Formula (III) described herein as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.

Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

In some embodiments, pharmaceutical composition comprising at least one compound of any of Formula (I), Formula (II), or Formula (III) illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

In certain embodiments, useful aqueous suspension contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound of any of Formula (I), Formula (II), or Formula (III). The term “solubilizing agent” generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example Polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.

Still other useful compositions may include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

Methods of Dosing and Treatment Regimens

In one embodiment, the compound of any of Formula (I), Formula (II), or Formula (III) are used in the preparation of medicaments for the treatment of PGD₂-dependent or PGD₂-mediated diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound of any of Formula (I), Formula (II), or Formula (III) or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a subject already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the subject's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.

In prophylactic applications, compositions containing the compounds described herein are administered to a subject susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the subject's state of health, weight, and the like. When used in a subject, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the subject's health status and response to the drugs, and the judgment of the treating physician.

In certain embodiments wherein the subject's condition does not improve, upon the doctor's discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the subject's life in order to ameliorate or otherwise control or limit the symptoms of the subject's disease or condition.

In certain embodiments wherein a subject's status does improve, administration of the compounds is given continuously; or, alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

Once improvement of the subject's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the subject requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

In some embodiments, compounds of Formula (I), (II) or (III) are administered chronically. In some embodiments, compounds of Formula (I), (II) or (III) are administered intermittently (e.g. drug holiday that includes a period of time in which the compound is not administered or is administered in a reduced amount). In some embodiments, compounds of Formula (I), (II) or (III) are administered in cycles that include: (a) a first period that includes daily administration of the compound of Formula (I), (II) or (III); followed by (b) a second period that includes a dose reduction of the daily amount of compound of Formula (I), (II) or (III) that is administered. In some embodiments, the compound of Formula (I), (II) or (III) is not administered in the second period. In some embodiments, the duration of the first and second periods, as well as the dose amounts are determined using methods described herein or known in the art.

The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment are typically in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

In certain embodiments, the pharmaceutical composition described herein is in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. In specific embodiments, the unit dosage is in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions are optionally packaged in single-dose non-re-closeable containers. Alternatively, multiple-dose re-closeable containers are used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection are, in some embodiments, presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

In one embodiment, the daily dosages appropriate for the compound of any of Formula (I), Formula (II), or Formula (III) described herein are from about 0.01 to about 10 mg/kg per body weight. In specific embodiments, an indicated daily dosage in a large mammal, including, but not limited to, humans, is in the range from about 0.5 mg to about 1000 mg, conveniently administered in divided doses, including, but not limited to, up to four times a day or in extended release form. In certain embodiments, suitable unit dosage forms for oral administration comprise from about 1 to 500 mg active ingredient. In other embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED₅₀ with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

The therapy of PGD₂-dependent or PGD₂-mediated diseases or conditions is designed to modulate the activity of DP₂, DP₁ and/or TP. Such modulation includes, in some embodiments, antagonizing DP₂ activity. In other embodiments, such modulation includes antagonizing DP₂ and DP₁. For example, in one embodiment, a DP₂ antgonist is administered in order to decrease signal transduction initiated by PGD₂ within the individual.

In accordance with one aspect, compositions and methods described herein include compositions and methods for treating, preventing, reversing, halting or slowing the progression of PGD₂-dependent or PGD₂ mediated diseases or conditions once it becomes clinically evident, or treating the symptoms associated with or related to PGD₂-dependent or PGD₂ mediated diseases or conditions, by administering to the subject a compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III). In certain embodiments, the subject already has a PGD₂-dependent or PGD₂ mediated disease or condition at the time of administration, or is at risk of developing a PGD₂-dependent or PGD₂ mediated disease or condition.

In certain aspects, the activity of DP₂ in a mammal is directly or indirectly modulated by the administration of (at least once) an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III) to a mammal. Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of DP₂. In additional aspects, the activity of PGD₂ in a mammal is directly or indirectly modulated, including reducing and/or inhibiting, by the administration of (at least once) an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III) to a mammal. Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of DP₂.

In one embodiment, prevention and/or treatment of PGD₂-dependent or PGD₂ mediated diseases or conditions comprises administering to a mammal at least once a therapeutically effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III). In specific embodiments, the compound administered to the mammal is a compound of any of Formula (I), Formula (II), or Formula (III). In some embodiments, there is provided a method of treating PGD₂-dependent or PGD₂ mediated diseases or conditions that include, but are not limited to, bone diseases and disorders, cardiovascular diseases and disorders, inflammatory diseases and disorders, immunological diseases or disorders, dermatological diseases and disorders, ocular diseases and disorders, cancer and other proliferative diseases and disorders, respiratory diseases and disorder, and non-cancerous disorders.

By way of example only, included in the prevention/treatment methods described herein are methods for treating respiratory diseases comprising administering to the mammal at least once an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III). By way of example, in some embodiments, the respiratory disease is asthma. Other respiratory diseases include, but are not limited to, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, allergic rhinitis, vascular responses, endotoxin shock, fibrogenesis, pulmonary fibrosis, allergic diseases, chronic inflammation, and adult respiratory distress syndrome.

By way of example only, included in such treatment methods are methods for preventing chronic obstructive pulmonary disease comprising administering to the mammal at least once an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III). In addition, chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis.

By way of example only, included in such treatment methods are methods for preventing increased mucosal secretion and/or edema in a disease or condition comprising administering to the mammal at least once an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for preventing or treating vasoconstriction, atherosclerosis and its sequelae myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and stroke comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for reducing cardiac reperfusion injury following myocardial ischemia and/or endotoxic shock comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for reducing the constriction of blood vessels in a mammal comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for lowering or preventing an increase in blood pressure of a mammal comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for preventing or treating eosinophil and/or basophil and/or dendritic cell and/or neutrophil and/or monocyte and/or T-cell recruitment comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for the prevention or treatment of abnormal bone remodeling, loss or gain, including diseases or conditions as, by way of example, osteopenia, osteoporosis, Paget's disease, cancer and other diseases comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for preventing ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for preventing otitis, otitis media comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for preventing CNS disorders comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III). CNS disorders include, but are not limited to, multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-surgical cognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain, spinal cord injury, cerebral edema and head injury.

By way of example only, included in the prevention/treatment methods described herein are methods for the treatment of cancer comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III), or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III). The type of cancer may include, but is not limited to, pancreatic cancer and other solid or hematological tumors.

By way of example only, included in the prevention/treatment methods described herein are methods for preventing or reducing the chances of endotoxic shock and septic shock comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein methods for preventing, treating or alleviating rheumatoid arthritis and osteoarthritis comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for preventing increased, reducing the incidences of or treating gastrointestinal diseases comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III). Such gastrointestinal diseases include, by way of example only, inflammatory bowel disease (IBD), colitis and Crohn's disease.

By way of example only, included in the prevention/treatment methods described herein are methods for the reduction or treatment of inflammation and/or preventing, reducing the incidences of or treating acute or chronic transplant rejection (including any vascular abnormality associated with acute or chronic rejection) or preventing or treating tumors or accelerating the healing of wounds comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for the prevention or treatment of rejection or dysfunction in a transplanted organ or tissue comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for treating type II diabetes comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for treating inflammatory responses of the skin comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III). Such inflammatory responses of the skin include, by way of example, psoriasis, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing and scarring. In another aspect are methods for reducing psoriatic lesions in the skin, joints, or other tissues or organs, comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for the treatment of cystitis, including, e.g., interstitial cystitis, comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

By way of example only, included in the prevention/treatment methods described herein are methods for the treatment of metabolic syndromes such as Familial Mediterranean Fever comprising administering at least once to the mammal an effective amount of at least one compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III).

Combination Treatments

In certain instances, it is appropriate to administer at least one compound of any of Formula (I), Formula (II), or Formula (III) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a subject upon receiving one of the compounds herein is inflammation, then it may be appropriate to administer an anti-inflammatory agent in combination with the initial therapeutic agent. Or, in one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the subject is enhanced). Or, in some embodiments, the benefit of experienced by a subject is increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. In one specific embodiment, the therapeutic benefit of treating asthma by administering at least one of the compounds described herein is increased by also providing the subject with other therapeutic agents or therapies for asthma. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the subject may simply be additive of the two therapeutic agents or the subject may experience a synergistic benefit.

In certain embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens can be determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a DP₂ antagonist described herein is initiated prior to, during, or after treatment with a second agent described above, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a DP₂ antagonist described herein and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the subject. For example, in one embodiment, a DP₂ antagonist described herein in the combination treatment is administered weekly at the onset of treatment, decreasing to biweekly, and decreasing further as appropriate.

Compositions and methods for combination therapy are provided herein. In accordance with one aspect, the pharmaceutical compositions disclosed herein are used to treat PGD₂-dependent or PGD₂ mediated conditions. In accordance with another aspect, the pharmaceutical compositions disclosed herein are used to treat respiratory diseases (e.g., asthma), where treatment with a DP₂ antagonist is indicated and to induce bronchodilation in a subject. In one embodiment, the pharmaceutical compositions disclosed herein are used to treat airways or nasal inflammation diseases such as asthma and rhinitis.

In one embodiment, pharmaceutical compositions disclosed herein are used to treat a subject suffering from a vascular inflammation-driven disorder. In one embodiment, the pharmaceutical compositions disclosed herein are used to treat skin inflammation diseases such as atopic dermatitis.

In certain embodiments, combination therapies described herein are used as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of a DP₂ described herein and a concurrent treatment. It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors. These factors include the type of respiratory disorder and the type of bronchoconstriction or inflammation from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more biologically active agents, the compound provided herein is administered either simultaneously with the biologically active agent(s), or sequentially. If administered sequentially, the attending physician decides on the appropriate sequence of administering protein in combination with the biologically active agent(s).

In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills). In one embodiment, one of the therapeutic agents is given in multiple doses, and in another, two (or more if present) are given as multiple doses. In some embodiments of non-simultaneous administration, the timing between the multiple doses vary from more than zero weeks to less than four weeks. In addition, the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations is also envisioned.

In additional embodiments, the compounds of any of Formula (I), Formula (II), or Formula (III) are used in combination with procedures that provide additional or synergistic benefit to the subject. By way of example only, subjects are expected to find therapeutic and/or prophylactic benefit in the methods described herein, wherein pharmaceutical composition of any of Formula (I), Formula (II), or Formula (III) and/or combinations with other therapeutics are combined with genetic testing to determine whether that individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions.

The compounds of any of Formula (I), Formula (II), or Formula (III) and combination therapies are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the compounds are initiated within the first 48 hours of the onset of the symptoms, preferably within the first 48 hours of the onset of the symptoms, more preferably within the first 6 hours of the onset of the symptoms, and most preferably within 3 hours of the onset of the symptoms. The initial administration is accomplished via any practical route, such as, for example, by intravenous injection, a bolus injection, infusion over 5 minutes to about 5 hours, a pill, a capsule, transdermal patch, buccal delivery, and the like, or combination thereof In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. In some embodiments, the length required for effective treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years, or from about 1 month to about 3 years.

By way of example, therapies which combine compounds of any of Formula (I), Formula (II), or Formula (III) with inhibitors of PGD₂ synthesis or PGD₂ receptor antagonists, either acting at the same or other points in the PGD₂ synthesis pathway, are encompassed herein for treating PGD₂-dependent or PGD₂ mediated diseases or conditions. In addition, by way of example, encompassed herein are therapies that combine compounds of any of Formula (I), Formula (II), or Formula (III) with inhibitors of inflammation for treating PGD₂-dependent or PGD₂ mediated diseases or conditions.

In another embodiment described herein, methods for treatment of PGD₂-dependent or PGD₂ mediated conditions or diseases include administration to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with an anti-inflammatory agent including, but not limited to, non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids (glucocorticoids). Anti-inflammatory agents include, but are not limited to: arthrotec, mesalamine, auralglan, sulfasalazine, daypro, etodolac, ponstan, and solumedrol; non-steroidal anti-inflammatory agents; corticosteroids; and leukotriene pathway modulators (e.g. montelukast, zilueton).

By way of example only, asthma is a chronic inflammatory disease characterized by pulmonary eosinophilia and airway hyperresponsiveness. In subjects with asthma, PGD₂ is released from mast cells, eosinophils, and basophils. PGD₂ is involved in contraction of airway smooth muscle, an increase in vascular permeability and mucus secretions, and has been reported to attract and activate inflammatory cells in the airways of asthmatics. Thus, in another embodiment described herein, the methods for treatment of respiratory diseases include administration to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with an anti-inflammatory agent.

NSAIDs include, but are not limited to: aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, flurobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, COX-2 specific inhibitors (such as, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L-745,337 and NS398).

Corticosteroids, include, but are not limited to: betamethasone (Celestone), prednisone (Deltasone), alclometasone, aldosterone, amcinonide, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacort, deoxycorticosterone, desonide, desoximetasone, desoxycortone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone, fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene, fluticasone, formocortal, halcinonide, halometasone, hydrocortisone/cortisol, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone, meprednisone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, paramethasone, prednicarbate, prednisone/prednisolone, rimexolone, tixocortol, triamcinolone, and ulobetasol.

In another embodiment described herein, methods for treatment of PGD₂-dependent or PGD₂ mediated conditions or diseases include administration to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination in combination with NSAIDs and NO-donors or NSAIDs and proton-pump inhibitors.

In another embodiment described herein, methods for treatment of PGD₂-dependent or PGD₂ mediated conditions or diseases includes administering to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with other PGD₂ receptor antagonists including, but are not limited to, DP₁ receptor antagonists and TP receptor antagonists. In another embodiment described herein, methods for treatment of PGD₂-dependent or PGD₂ mediated conditions or diseases includes administered to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with a DP₁ receptor antagonist. DP₁ receptor antagonists include, but are not limited to, BWA868C (Sharif et al., Br. J. Pharmacol., November 2000; 131(6): 1025-38), MK-0524 (Sturino et al, J. Med. Chem., 2007, 50, 794-806 and Cheng et al, PNAS, April 2006; 103(17):6682-7.) and S-5751 (Arimura et al., J. Pharmacol. Exp. Ther., August 2001; 298(2):411-9). For some subjects, the most appropriate formulation or method of use of such combination treatments depends on the type of PGD₂-dependent or PGD₂ mediated disorder, the time period in which the DP₂ antagonist acts to treat the disorder and/or the time period in which the DP₁ receptor antagonist acts to prevent DP₁ receptor activity. By way of example only, some embodiments described herein provide for such combination treatments that are used for treating a subject suffering from respiratory disorders such as asthma and rhinitis

In another embodiment described herein, methods for treatment of PGD₂-dependent or PGD₂ mediated conditions or diseases includes administering to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with a TP receptor antagonist. TP receptor antagonists include, but are not limited to, Ramatroban (“Bayer™”), GR32191 (Beasley et al., J. Appl. Physiol., April 1989; 66(4):1685-93), ICH92605 (Boersma et al., Br. J. Pharmacal., December 1999; 128(7):1505-12) and derivatives or analogs thereof. Such combinations may be used to treat PGD₂-dependent or PGD₂ mediated disorders, including respiratory disorders.

In one embodiment, the co-administration of a DP₂ receptor antagonist with a DP₁ receptor antagonist or a TP receptor antagonist has therapeutic benefit over and above the benefit derived from the administration of a either a DP₂ antagonist, DP₁ antagonist or a TP antagonist alone. In the case that substantial inhibition of PGD₂ activity has undesired effects, partial inhibition of this pathway through the amelioration of the effects of the proinflammatory agonists combined with the block of the DP₁ receptor, TP receptor and/or DP₂ receptor may afford substantial therapeutic benefits, particularly for respiratory diseases.

In another embodiment described herein, methods for treatment of PGD₂-dependent or PGD₂ mediated conditions or diseases, such as proliferative disorders, including cancer, comprises administration to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected, by way of example only, alemtuzumab, arsenic trioxide, asparaginase (pegylated or non-), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin, irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, Paclitaxel™, taxol, temozolomide, thioguanine, or classes of drugs including hormones (an antiestrogen, an antiandrogen, or gonadotropin releasing hormone analogues, interferons such as alpha interferon, nitrogen mustards such as busulfan or melphalan or mechlorethamine, retinoids such as tretinoin, topoisomerase inhibitors such as irinotecan or topotecan, tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents to treat signs or symptoms induced by such therapy including allopurinol, filgrastim, granisetron/ondansetron/palonosetron, dronabinol.

In another embodiment described herein, methods for treatment of PGD₂-dependent or PGD₂ mediated conditions or diseases, such as the therapy of transplanted organs or tissues or cells, comprises administration to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from, by way of example only, azathioprine, a corticosteroid, cyclophosphamide, cyclosporin, dacluzimab, mycophenolate mofetil, OKT3, rapamycin, tacrolimus, thymoglobulin.

In another embodiment described herein, methods for treatment of PGD₂-dependent or PGD₂ mediated conditions or diseases, such as atherosclerosis, comprises administration to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected, by way of example only, HMG-CoA reductase inhibitors (e.g., statins in their lactonized or dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof, including but not limited to lovastatin; simvastatin; dihydroxy open-acid simvastatin, particularly the ammonium or calcium salts thereof; pravastatin, particularly the sodium salt thereof; fluvastatin, particularly the sodium salt thereof; atorvastatin, particularly the calcium salt thereof; nisvastatin, also referred to as NK-104; rosuvastatin); agents that have both lipid-altering effects and other pharmaceutical activities; HMG-CoA synthase inhibitors; cholesterol absorption inhibitors such as ezetimibe; cholesterol ester transfer protein (CETP) inhibitors, for example JTT-705 and CP529, 414; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors); acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors of ACAT-1 and-2; microsomal triglyceride transfer protein (MTP) inhibitors; probucol; niacin; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; platelet aggregation inhibitors, for example glycoprotein IIb/IIIa fibrinogen receptor antagonists and aspirin; human peroxisome proliferator activated receptor gamma (PPARγ) agonists, including the compounds commonly referred to as glitazones, for example troglitazone, pioglitazone and rosiglitazone and including those compounds included within the structural class known as thiazolidinediones as well as those PPARγ agonists outside the thiazolidinedione structural class; PPARαagonists such as clofibrate, fenofibrate including micronized fenofibrate, and gemfibrozil; PPAR dual α/γ agonists such as 5-[(2, 4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide, known as KRP-297; vitamin B6 (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HCI salt; vitamin B12 (also known as cyanocobalamin); folic acid or a pharmaceutically acceptable salt or ester thereof such as the sodium salt and the methylglucamine salt; anti-oxidant vitamins such as vitamin C and E and beta carotene; beta-blockers; angiotensin II antagonists such as losartan; angiotensin converting enzyme inhibitors such as enalapril and captopril; calcium channel blockers such as nifedipine and diltiazam; endothelian antagonists; agents that enhance ABC1 gene expression; FXR and LXR ligands including both inhibitors and agonists; bisphosphonate compounds such as alendronate sodium; and cyclooxygenase-2 inhibitors such as rofecoxib and celecoxib.

In another embodiment described herein, methods for treatment of PGD₂-dependent or PGD₂ mediated conditions or diseases, such as the therapy of stroke, comprises administration to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from, by way of example only, COX-2 inhibitors; nitric oxide synthase inhibitors, such as N-(3-(aminomethyl)benzyl)acetamidine; Rho kinase inhibitors, such as fasudil; angiotension II type-1 receptor antagonists, including candesartan, losartan, irbesartan, eprosartan, telmisartan and valsartan; glycogen synthase kinase 3 inhibitors; sodium or calcium channel blockers, including crobenetine; p38 MAP kinase inhibitors, including SKB 239063; thromboxane AX-synthetase inhibitors, including isbogrel, ozagrel, ridogrel and dazoxiben; statins (HMG CoA reductase inhibitors), including lovastatin, simvastatin, dihydroxy open-acid simvastatin, pravastatin, fluvastatin, atorvastatin, nisvastatin, and rosuvastatin; neuroprotectants, including free radical scavengers, calcium channel blockers, excitatory amino acid antagonists, growth factors, antioxidants, such as edaravone, vitamin C, TROLOX™, citicoline and minicycline, and reactive astrocyte inhibitors, such as (2R)-2-propyloctanoic acid; beta andrenergic blockers, such as propranolol, nadolol, timolol, pindolol, labetalol, metoprolol, atenolol, esmolol and acebutolol; NMDA receptor antagonists, including memantine; NR2B antagonists, such as traxoprodil; 5-HT1A agonists; receptor platelet fibrinogen receptor antagonists, including tirofiban and lamifiban; thrombin inhibitors; antithrombotics, such as argatroban; antihypertensive agents, such as enalapril; vasodilators, such as cyclandelate; nociceptin antagonists; DPN antagonists; CETP inhibitors; GABA 5 inverse agonists; and selective androgen receptor modulators.

In another embodiment described herein, methods for treatment of PGD₂-dependent or PGD₂ mediated conditions or diseases, such as the therapy of pulmonary fibrosis, comprises administration to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from, by way of example only, anti-inflammatory agents, such as corticosteroids, azathioprine or cyclophosphamide.

In another embodiment described herein, methods for treatment of PGD₂-dependent or PGD₂ mediated conditions or diseases, such as the therapy of interstitial cystitis, comprises administration to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from, by way of example only, dimethylsulfoxide, omalizumab, and pentosan polysulfate.

In another embodiment described herein, methods for treatment of PGD₂-dependent or PGD₂ mediated conditions or diseases, such as the therapy of disorders of bone, comprises administration to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from the, by way of example only, minerals, vitamins, bisphosphonates, anabolic steroids, parathyroid hormone or analogs, and cathepsin K inhibitors.

In yet another embodiment described herein, methods for treating PGD₂-dependent or PGD₂ mediated conditions or diseases, such as the therapy of respiratory disorders (e.g., asthma, COPD and rhinitis), comprises administration to a patient compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one respiratory agent. Respiratory agents include, but are not limited to, bronchodilators (e.g., sympathomimetic agents and xanthine derivatives), leukotriene receptor antagonists, leukotriene formation inhibitors, leukotriene modulators, nasal decongestants, respiratory enzymes, lung surfactants, antihistamines (e.g., Mepyramine (pyrilamine), Antazoline, Diphenhydramine, Carbinoxamine, Doxylamine, Clemastine, Dimenhydrinate, Pheniramine, Chlorphenamine (chlorpheniramine), Dexchlorpheniramine, Brompheniramine, Triprolidine, cetirizine, Cyclizine, Chlorcyclizine, Hydroxyzine, Meclizine, loratadine, desloratidine, Promethazine, Alimemazine (trimeprazine), Cyproheptadine, Azatadine, Ketotifen, Acrivastine, Astemizole, Cetirizine, Mizolastine, Terfenadine, Azelastine, Levocabastine, Olopatadine, Levocetirizine, Fexofenadine), mucolytics, corticosteroids, glucocorticoids, anticholinergics, antitussives, analgesics, expectorants, albuterol, ephedrine, epinephrine, fomoterol, metaproterenol, terbutaline, budesonide, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, ipratropium bromide, pseudoephedrine, theophylline, montelukast, zafirlukast, pranlukast, tomelukast, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan, iloprost, treprostinil, pirfenidone, FLAP inhibitors, FLAP modulators, 5-LO inhibitors, BLT1 receptor antagonists and BLT2 receptor antagonists.

In a specific embodiment described herein, methods for treating PGD₂-dependent or PGD₂ mediated conditions or diseases, such as the therapy of asthma and/or COPD, comprises administration to a patient anti-inflammatory agents. In certain embodiments, methods for treating PGD₂-dependent or PGD₂ mediated conditions or diseases, such as the therapy of asthma and/or COPD, comprise administration to a patient compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from, but not limited to, epinephrine, isoproterenol, orciprenaline, bronchodilators, glucocorticoids, leukotriene modifiers, mast-cell stabilizers, xanthines, anticholinergics, β-2 agonists, FLAP inhibitors, FLAP modulators or 5-LO inhibitors. β-2 agonists include, but are not limited to, short-acting β-2 agonists (e.g., salbutamol (albuterol), levalbuterol, terbutaline, pirbuterol, procaterol, metaproterenol, fenoterol and bitolterol mesylate) and long-acting β-2 agonists (e.g., salmeterol, formoterol, bambuterol and clenbuterol). FLAP inhibitors and/or FLAP modulators include, but are not limited to, 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, MK-886, MK-0591, DG-031 (BAY-x1005) and compounds found in US 2007/0225285, US 2007/0219206, US 2007/0173508, US 2007/0123522 and US 2007/0105866 (each of which are hereby incorporated by reference). Glucocorticoids include, but are not limited to, beclometasone, budesonide, ciclesonide, fluticasone and mometasone. Anticholinergics include, but are not limited to, ipratropium and tiotropium. Mast cell stabilizers include, but are not limited to, cromoglicate and nedocromil. Xanthines include, but are not limited to, amminophylline, theobromine and theophylline. Leukotriene antagonists include, but are not limited to, montelukast, tomelukast, pranlukast and zafirlukast. 5-LO inhibitors include, but are not limited to, zileuton, VIA-2291 (ABT761), MK-0633, CJ-13,610 (PF-4191834), AZ-4407 and ZD-2138 and compounds found in US 2007/0149579, WO2007/016784.

In another specific embodiment described herein, methods for treating PGD₂-dependent or PGD₂ mediated conditions or diseases, such as the therapy of rhinitis, comprises administration to a subject compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from, by way of example only, antihistamines, leukotriene antagonists, corticosteroids and decongestants. Leukotriene antagonists include, but are not limited to, montelukast, tomelukast, pranlukast and zafirlukast.

In another aspect, methods for treating PGD₂-dependent or PGD₂ mediated conditions or diseases, iclude administering a DP₂ antagonist described herein in combination with other agents to treat respiratory diseases or conditions. Therapeutic agents used in the treatment of respiratory conditions and disorders, such as, but not limited to asthma, include: glucocorticoids, such as, ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone; leukotriene modifiers, such as, montelukast, zafirlukast, pranlukast, and zileuton; mast cell stabilizers, such as, cromoglicate (cromolyn), and nedocromil; antimuscarinics/anticholinergics, such as, ipratropium, oxitropium, and tiotropium; methylxanthines, such as, theophylline and aminophylline; antihistamine, such as, mepyramine (pyrilamine), antazoline, diphenhydramine, carbinoxamine, doxylamine, clemastine, dimenhydrinate, pheniramine, chlorphenamine (chlorpheniramine), dexchlorphenamine, brompheniramine, triprolidine, cyclizine, chlorcyclizine, hydroxyzine, meclizine, promethazine, alimemazine (trimeprazine), cyproheptadine, azatadine, ketotifen, acrivastine, astemizole, cetirizine, loratadine, mizolastine, terfenadine, fexofenadine, levocetirizine, desloratadine, fexofenadine; omalizumab, an IgE blocker; beta2-adrenergic receptor agonists, such as: short acting beta2-adrenergic receptor agonists, such as, salbutamol (albuterol), levalbuterol, terbutaline, pirbuterol, procaterol, metaproterenol, fenoterol, bitolterol mesylate; and long-acting beta2-adrenergic receptor agonists, such as, salmeterol, formoterol, bambuterol.

In one aspect, DP₂ anatogonists described herein are admistered in combination with one or more agents used to treat used to treat asthma, including, but not limited to: combination inhalers (fluticasone and salmeterol oral inhalation (e.g. Advair)); inhaled Beta-2 agonists (albuterol inhaler; albuterol nebulizer solution; formoterol; isoproterenol oral inhalation; levalbuterol; metaproterenol inhalation; pirbuterol acetate oral inhalation; salmeterol aerosol inhalation; salmeterol powder inhalation; terbutaline inhaler); inhaled corticosteroids (beclomethasone oral inhalation; budesonide inhalation solution; budesonide inhaler; flunisolide oral inhalation; fluticasone inhalation aerosol; fluticasone powder for oral inhalation; mometasone inhalation powder; triamcinolone oral inhalation); leukotriene modifiers (montelukast; zafirlukast; pranlukast; tomelukast; zileuton); mast cell stabilizers (cromolyn inhaler; nedocromil oral inhalation); monoclonal antibodies (omalizumab); oral Beta-2 agonists (albuterol oral syrup; albuterol oral tablets; metaproterenol; terbutaline); bronchodilator (aminophylline; oxtriphylline; theophylline).

In one aspect, DP₂ anatogonists described herein are admistered in combination with one or more agents used to treat allergy, including, but not limited to: antihistamine and decongestant combinations (cetirizine and pseudoephedrine; desloratadine and pseudoephedrine ER; fexofenadine and pseudoephedrine; loratadine and pseudoephedrine); antihistamines (azelastine nasal spray; brompheniramine; brompheniramine oral suspension; carbinoxamine; cetirizine; chlorpheniramine; clemastine; desloratadine; dexchlorpheniramine ER; dexchlorpheniramine oral syrup; diphenhydramine oral; fexofenadine; loratadine; promethazine); decongestants (pseudoephedrine); leukotriene modifiers (montelukast; montelukast granules); nasal anticholinergics (ipratropium); nasal corticosteroids (beclomethasone nasal inhalation; budesonide nasal inhaler; flunisolide nasal inhalation; fluticasone nasal inhalation; mometasone nasal spray; triamcinolone nasal inhalation; triamcinolone nasal spray); nasal decongestants (phenylephrine); nasal mast cell stabilizers (cromolyn nasal spray).

In one aspect, DP₂ anatogonists described herein are admistered in combination with one or more agents used to treat chronic obstructive pulmonary disease (COPD), including, but not limited to: anticholinergics—ipratropium bromide oral inhalation); combination Inhalers (albuterol and ipratropium (e.g. Combivent, DuoNeb); fluticasone and salmeterol oral inhalation (e.g. Advair)); corticosteroids (dexamethasone tablets; fludrocortisone acetate; hydrocortisone tablets; methylprednisolone; prednisolone liquid; prednisone oral; triamcinolone oral); inhaled Beta-2 Agonists (albuterol inhaler; albuterol nebulizer solution; formoterol; isoproterenol oral inhalation; levalbuterol; metaproterenol inhalation; pirbuterol acetate oral inhalation; salmeterol aerosol inhalation; salmeterol powder inhalation; terbutaline inhaler); inhaled Corticosteroids (beclomethasone oral inhalation; budesonide inhalation solution; budesonide inhaler; flunisolide oral inhalation; fluticasone inhalation aerosol; fluticasone powder for oral inhalation; triamcinolone oral inhalation); mukolytics (guaifenesin); oral Beta-2 agonists (albuterol oral syrup; albuterol oral tablets; metaproterenol; terbutaline); bronchodilator (aminophylline; oxtriphylline; theophylline).

In one embodiment, DP₂ anatogonists described herein are administered to a subject in combination with inhaled corticosteroids.

In one embodiment, DP₂ anatogonists described herein are administered to a subject in combination with beta2-adrenergic receptor agonists. In one embodiment, DP₂ anatogonists described herein are administered to a subject in combination with short acting beta2-adrenergic receptor agonists. In one embodiment, DP₂ anatogonists described herein are administered to a subject in combination with long-acting beta2-adrenergic receptor agonists.

As discussed herein, the administration of compounds of any of Formula (I), Formula (II), or Formula (III) is designed to anatagonize the activity of DP₂. For example, in specific embodiments, the administration of a DP₂ inhibitor decreases signal transduction initiated by PGD₂ within the individual

Thus, in accordance with one aspect, methods described herein include the diagnosis or determination of whether or not a subject is suffering from a PGD₂-dependent or PGD₂ mediated disease or condition by administering to the subject a compound of any of Formula (I), Formula (II), or Formula (III) or pharmaceutical composition or medicament which includes a compound of any of Formula (I), Formula (II), or Formula (III) and determining whether or not the subject responds to the treatment.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from any acceptable material including, e.g., glass or plastic.

For example, the container(s) can comprise one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.

A kit will typically comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein.

EXAMPLES

These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

Example 1 Synthesis of {3-[Carboxymethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-acetic acid (Compound 1-1)

Step 1: A solution of (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazole (Rosentreter et al, Arzneim.-Forsch./Drug Res., 1989, 39, p 1519; 0.111 g, 0.32 mmol) in DMF (5 mL) was treated with NaH (60% dispersion; ˜0.020 g, ˜0.39 mmol) for 30 minutes at room temperature. Ethyl bromoacetate (71 μL, 0.65 mmol) was added and the mixture stirred overnight. The solution was poured into water, extracted with EtOAc (×2), washed with water (×2) and brine (×2), dried over MgSO₄, and concentrated to give an oil (0.160 g). This oil was dissolved in THE (3 mL), MeOH (3 mL) and 1N aqueous NaOH (3 mL) and stirred overnight. Purification by reverse phase preparative HPLC provided the title compound. [M+H]⁺=461.

Example 2 Synthesis of {(4-Fluoro-benzenesulfonyl)-[9-(3-hydroxy-3-methyl-butyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino}-acetic acid (Compound 1-2), 3-{3-[(4-Fluoro-benzenesulfonyl)-(2-hydroxy-2-methyl-propyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionic acid (Compound 1-3), and 4-FluoroN-[9-(3-hydroxy-3-methyl-butyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N-(2-hydroxy-2-methyl-propyl)-benzenesulfonamide (Compound 1-4)

Step 1:

A solution of (3R)-3-(4-fluorophenylsulfonylamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid sodium salt (Rosentreter et al, Arzneim.-Forsch./Drug Res., 1989, 39, p 1519; 0.150 g, 0.34 mmol) in DMF (3 mL) was treated with NaH (60% dispersion; 0.016 g, 0.41 mmol) for 30 minutes at 0° C. Methyl bromoacetate (35 μL, 0.38 mmol) was added and the mixture stirred for a further 30 minutes. The solution was poured into water, extracted with EtOAc (×2), washed with water (×3), dried over MgSO₄, and concentrated. The residue was purified by column chromatography (silica gel) to give 0.192 g of the O- and N-bis-alkylated product.

Step 2:

The bis-alkylated product (0.187 g, 0.33 mmol) in THF (3.6 mL) at 0° C. was treated with methyl magnesium iodide (3M in ether; 445 μL, 1.34 mmol) and the reaction was allowed to warm to room temperature over 3 hours. The mixture was quenched with saturated aqueous NH₄Cl and extracted with EtOAc (×2). The organic layer was dried over MgSO₄, concentrated and the residue dissolved in THF (5 mL) and 1N aqueous LiOH (5 mL) and stirred for 72 hours. The mixture was quenched with saturated aqueous NH₄Cl and extracted with EtOAc (×2). Purification of the mixture by reverse phase prep HPLC provided the title compounds. Mass spectrometric data: Compound 1-2 [M+H]⁺=489; Compound 1-3 [M+H]⁺=489; Compound 1-4 [M+H]⁺=503.

Example 3 Synthesis of 3-{3-[Carbamoylmethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionic acid (Compound 1-5)

Step 1.

A solution of (3R)-3-(4-fluorophenylsulfonylamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid sodium salt (Rosentreter et al, Arzneim.-Forsch./Drug Res., 1989, 39, p 1519; 0.150 g, 0.34 mmol) in DMF (3 mL) was treated with NaH (60% dispersion; 0.035 g, 0.41 mmol) for 30 minutes at 0° C. Bromo acetonitrile (26 μL, 0.38 mmol) was added and the mixture stirred for a further 30 minutes. The solution was poured into water, extracted with EtOAc (×2), washed with water (×3), dried over MgSO₄, and concentrated. The residue was purified by column chromatography (silica gel) to give 0.050 g of a mixture containing the O- and N-bis-alkylated product.

Step 2.

The bis-alkylated product (0.050 g) in MeOH (2 mL) at room temperature was treated with concentrated HCl (3 mL) and the reaction was heated to 60° C. for 3 hours. The mixture was concentrated in vacuo, and the residue was dissolved in THF (3 mL) and 1N aqueous LiOH (3 mL) and stirred for 16 hours. The mixture was quenched with 1N aqueous HCl (to pH=3) and extracted with EtOAc (×3). Purification of the mixture by reverse phase preparative HPLC provided the title compound. [M+H]⁺=474.

Example 4 Synthesis of 3-{3-[Carboxymethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionic acid (Compound 1-6)

Step 1:

A solution of (3R)-3-(4-fluorophenylsulfonylamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid sodium salt (Rosentreter et al, Arzneim.-Forsch./Drug Res., 1989, 39, p 1519; 0.150 g, 0.34 mmol) in DMF (3 mL) was treated with NaH (60% dispersion; 0.016 g, 0.41 mmol) for 30 minutes at 0° C. Methyl bromoacetate (35 μL, 0.38 mmol) was added and the mixture stirred for a further 30 minutes. The solution was poured into water, extracted with EtOAc (×2), washed with water (×3), dried over MgSO₄, and concentrated. The residue was purified by column chromatography (silica gel) to give 0.192 g of the O- and N-bis-alkylated product.

Step 2:

The bis-alkylated product (0.34 mmol) in THF (2 mL) and 1N aqueous LiOH (2 mL) was stirred overnight. After acidification with 1N aqueous HCl (to pH˜3) the mixture was extracted with EtOAc (×3). Purification of the mixture by reverse phase prep HPLC provided the title compound. [M+H]⁺=475.

Example 5a DP₂/CRTH2 Binding Assay

The ability of a compound to bind to the human DP₂ receptor is assessed via a radioligand binding assay using [³H]PGD₂. HEK293 cells stably expressing recombinant human DP₂ are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT, lysed and centrifuged at 75,000×g to pellet the membranes. The membranes are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT and 10% glycerol to approximately 5 mg protein/ml. Membranes (2-10 μg protein/well) are incubated in 96-well plates with 1 nM [³H]PGD₂ and test compound in Assay Buffer (50 mM Hepes, 10 mM MnCl₂, 1 mM EDTA, plus or minus 0.2% human serum albumin, pH 7.4) for 60 minutes at room temperature. The reactions are terminated by rapid filtration through Whatman GF/C glass fibre filter plates. The filter plates were pre-soaked in 0.33% polythylenimine for 30 minutes at room temperature then washed in Wash Buffer (50 mM Hepes, 0.5 M NaCl pH 7.4) prior to harvesting. After harvesting, the filter plates are washed 3 times with 1 ml cold Wash Buffer then dried. Scintillant is then added to the plates and the radioactivity retained on the filters is determined on a Packard TopCount (Perkin Elmer). Specific binding is determined as total radioactive binding minus non-specific binding in the presence of 10 μM PGD₂. IC₅₀s were determined using GraphPad prism analysis of drug titration curves. Compounds tested had an IC₅₀ of less than 100 micromolar in this assay.

Example 5b GTPγS Binding Assay

The ability of a compound to inhibit binding of GTP to DP₂ is assessed via a membrane GTPγS assay. CHO cells stably expressing the recombinant human CRTH2 receptor are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT, lysed and centrifuged at 75,000×g to pellet the membranes. The membranes are resuspended in 10 mM Hepes, 7.4 containing 1 mM DTT and 10% glycerol. Membranes (˜12.5 μg per well) are incubated in 96-well plates with 0.05 nM [³⁵S]-GTPγS, 80 nM PGD₂, 5 μM GDP, and test compound in Assay Buffer (50 mM Hepes, pH 7.4, 100 mM NaCl, 5 mM MgCl₂ and 0.2% human serum albumin) for 60 minutes at 30° C. The reactions are terminated by rapid filtration through Whatman GF/B glass fibre filter plates. The filter plates are washed 3 times with 1 ml cold Assay Buffer and dried. Scintillant is then added to the plates and the radioactivity retained on the filters is determined on a Packard TopCount (Perkin Elmer). Specific binding is determined as total radioactive binding minus non-specific binding in the absence of the ligand (80 nM PGD₂). IC₅₀s were determined using Graphpad prism analysis of drug titration curves.

Example 5c Whole Blood Esoinophil Shape Change Assay

Blood is drawn from consenting human volunteers in EDTA vacutainer tubes and used within 1 hr of draw. A 98 μl aliquot of blood is mixed with 2 μl of test compound (in 50% DMSO) in 1.2 ml polypropylene tubes. The blood is vortexed and incubated at 37° C. for 15 minutes. 5 μl of 1 μM PGD₂ in PBS is added for a final concentration of 50 nM and the tubes briefly vortexed. The reactions are incubated for exactly 5 minutes at 37° C. and then terminated by placing the tubes on ice and immediately adding 250 μl of ice-cold 1:4 diluted Cytofix (BD Biosciences). The reactions are transferred to 12×75 mM polystyrene round bottom tubes and the red blood cells lysed by the addition of 3 ml ammonium chloride lysing solution (150 mM NH₄Cl, 10 mM KHCO₃, 0.1 mM EDTA disodium salt) and incubation at room temperature for 15 minutes. The cells are pelleted by spinning at 1300 rpm for 5 minutes at 4° C. and washed once with 3 ml ice-cold PBS. The cells are resuspended in 0.2 ml of ice-cold 1:4 diluted Cytofix (BD Biosciences) and analyzed on a FACSCalibur (BD Biosciences) within 2 hours. Eosinophils were gated on the basis of autofluorescence in the FL2 channel and shape change on 500 eosinophils was assayed by forward scatter and side scatter analysis. The specific change in shape induced by PGD₂ was calculated as the difference between the percentage of high forward scatter eosinophils in the presence and absence of PGD₂. IC₅₀s were determined using Graphpad Prism® analysis of drug titration curves.

Example 5d DP₁ Binding Assay

The ability of a compound to bind to the human DP1 receptor was evaluated via a radioligand membrane binding assay using the DP₁ selective synthetic ligand [³H]BWA868C. Packed human platelets (Biological Specialty Corporation), were resuspended in 6 volumes of Hepes/HBSS buffer (10 mM Hepes, 1 mM DTT in Hanks Balanced Salt Solution (HBSS), lysed and centrifuged at 75,000×g to pellet the membranes. Membranes were resuspended in Hepes/HBSS buffer to approximately 12 mg protein/ml. Membranes (20 μg protein/well) are incubated in 96-well plates with 2 nM [³H]BWA868C and test compound in Assay Buffer (50 mM Hepes, 10 mM MnCl₂, 1 mM EDTA, plus or minus 0.2% human serum albumin, pH 7.4) for 60 minutes at room temperature. The reactions are terminated by rapid filtration through Whatman GF/C glass fibre filter plates. The filter plates were pre-soaked in 0.33% polethylenimine for 30 minutes at room temperature then washed in Wash Buffer (50 mM Hepes, 0.5 M NaCl pH 7.4) prior to harvesting. After harvesting, the filter plates are washed 3 times with 1 ml cold Wash Buffer then dried. Scintillant is then added to the plates and the radioactivity retained on the filters is determined on a Packard TopCount (Perkin Elmer). Specific binding is determined as total radioactive binding minus non-specific binding in the presence of 10 μM BW A868C. IC₅₀s were determined using GraphPad prism analysis of drug titration curves.

Example 6 Mouse Allergic Rhinitis Model

The compounds ability to inhibit allergen-induced sneezing and nasal rubbing is assessed using a mouse model of allergic rhinitis. Methods were adapted from those detailed in Nakaya, M., et al. 2006, Laboratory Investigation, 86:917-926. Female BALB/c mice (20-25 g) are immunized by an intraperitoneal injection (i.p.) of 2 μg ovalbumin (OVA) complexed with alum in a volume 0.2 ml on days 0 and 14. Seven days later (day 21) mice are challenged intranasally with 20 μl of a 10 mg/ml solution of OVA. The challenge period occurs daily from days 21 to day 25. Mice (5-7/group) are randomly assigned to receive either compound or vehicle and are treated by oral gavage 1-2 hour prior to each OVA challenge. The number of sneezes and nasal rubs are counted by an independent blind observe during a period of 8 minutes immediately following OVA challenge on days 21, 23 and 25. A significant increase in allergen-induced sneezing and nasal rubbing occurs over the 5-day challenge period. Inhibition of this effect by select compounds is determined statistically using Graphpad prism.

Example 7 Guinea Pig IV-DKPGD2-Induced Peripheral Blood Leukocyte Influx

The compounds ability to inhibit leukocyte migration in vivo was assessed using intravenous injection of 13,14-dihydro-15-keto-prostaglandin D2 (DK-PGD2). Methods were adapted from those detailed Shichijo et al., 2003, Journal of Pharmacology and Experimental Therapeutics, 307:518-525. Male Hartley guinea pigs were immunized with ovalbumin (OVA) on day 0 by intraperitoneal (IP) injection of 1 ml of a 100 μg/ml solution in Imject Alum. They were then used in the DK-PGD2 procedure between days 14 and 21. Subjects were randomly assigned to receive either vehicle (0.5% methyl cellulose, 4 ml/kg, oral (PO)) or one of three to four doses of test compound. Two hours or eighteen hours after dosing, animals were anesthetized with ketamine and challenged with DK-PGD2 (1 mg/kg, IV). Thirty minutes after IV administration, blood was collected via the marginal ear vein into EDTA tubes for cell analysis. 10 μl blood was lysed in 190 μl water followed by a further 20-fold dilution in PBS. A 10 μl fraction was mixed with equal parts trypan blue and loaded on a hemocytometer. Cells were visualized at a magnification of 40× using a LabPro light microscope and totals counted and recorded. Cells are expressed as total cells×10⁸ per ml of blood. Inhibition of this effect by select compounds is determined statistically using Graphpad prism.

The compounds of Formula (I), Formula (II), or Formula (III) that were tested in Table 2 had IC₅₀ below 10 μM in the CRTH2 binding assay.

TABLE 2 Representative Biological Data Compound hDP2 μM hDP1 μM 1-1 A C 1-2 C C 1-3 C C 1-4 C C 1-5 C C 1-6 C C Ramatroban B C A = less than 0.3 μM; B = greater than 0.3 μM; C = greater than 1 μM.

Example 8 Clinical Trials in Humans

Study 1: Clinical Trial Evaluating Effect of Compound of Formula (I) on ex vivo PGD2-Induced Blood Eosinophil Shape Change

In this double-blind, randomized, placebo-controlled, single ascending dose study of Compound of Formula (I), (II), or (III) in healthy volunteers the inhibition of ex vivo PGD2-induced blood eosinophil shape change is determined to show proof of biochemical mechanism of DP2 receptor antagonism. Eight subjects (6 active, 2 placebo) per dose level are used. Pre dose blood is drawn and challenged with PGD2 to determine baseline shape change as described above in Example 5. At varying times after dosing blood is drawn for both pharmacokinetic analyses of drug concentration in blood, and also for PGD2 challenge and eosinophil shape change determination. The extent of receptor blockage is determined from the relationship between drug blood concentration and percentage inhibition of eosinophil shape change.

Study 2: Clinical Trial Evaluating Effect of Compound of Formula (I), (II), or (III) on Allergen-Induced Nasal Symptoms and Inflammatory and Allergic Biomarkers

In this double-blind, randomized, placebo-controlled study of Compound of Formula (I), (II), or (III) in individuals with allergic rhinitis the inhibition of nasal symptoms and allergic biomarkers is determined following nasal challenge with appropriate allergen. Fifteen subjects (10 active, 5 placebo) are used. Subjects are dosed for 7 days with either placebo or an amount of compound of Formula (I), (II), or (III) that results in complete DP2 receptor block in an ex vivo PGD2-induced blood eosinophil shape change pharmacodynamic study as described above. On day 7 subjects undergo nasal allergen challenge (2 hours post-dose) and early allergic response (0.25-1.0 hr) and late allergic response (4-24 hr) are evaluated as an increase from baseline for treated vs placebo. In addition changes in inflammatory cell differentials, Th2 cytokines and other inflammatory markers are determined as increase from baseline for treated vs. placebo.

Compound of Formula (I), (II), or (III) Assay

The plasma concentrations of compound of Formula (I), (II), or (III) are determined by gas chromatography, giving a detection limit of 1 ng·ml-1 (Ritter W. Determination of BAY u3405, a novel thromboxane antagonist, in plasma and urine by HPLC and GC. In: Reid E, Wilson I D, eds. Bioanalytical Approaches for Drugs, Including Anti-asthmatics and Metabolites. Methodological Surveys in Biochemistry and Analysis, 1992; 22: 211-216).

Study 3—Vienna Challenge Chamber Study

Study design: The study is a randomised, double blind, placebo controlled, two way crossover evaluation of compound of Formula (I), (II), or (III), given orally for eight days. There is a screening period of one week and a washout period of three weeks between the two treatment periods.

There is a follow up one week after the last dose of study drug. The group of patients who receive the study drug for the first treatment period and placebo for the second are designated group A, while the group of patients who receive placebo for the first treatment period and the study drug for the second treatment period are designated group B.

Treatment plan and methods: The subjects undergo a complete screening assessment to determine a baseline response to allergens. This screening assessment takes place one week prior to the start of dosing.

Subjects commence dosing with compound of Formula (I), (II), or (III), or placebo on Day 1 of each treatment period of the study. Adverse events, total nasal symptom score and concomitant medications are noted.

Subjects report back to the clinic on Day 2 of each treatment period for a 6 hour allergen challenge. The following measurements are obtained:

-   -   Total nasal symptom score (TNSS) (obstruction, rhinorrhoea,         itch, sneeze) with each symptom scored on a categorical scale         from 0 to 3 pre-challenge, every 15 mins from 0 to 6 h         post-start of challenge     -   Eye symptom score (watery eyes, itchy eyes, red eyes) with each         symptom scored on a categorical scale from 0 to 3 pre-challenge,         every 15mins from 0 to 6 h post-start of challenge     -   Other symptoms (cough, itchy throat, itchy ears) with each         symptom scored on a categorical scale from 0 to 3 pre-challenge         and every 15mins from 0 to 6 h post-start of challenge

Subjects report back to the clinic on Day 8 of each treatment period for a 6 hour allergen challenge and the measurements obtained on Day 2 are repeated.

A final follow-up visit is conducted one after the last dose of test article in Treatment Period 2.

Pharmaceutical Compositions Example 9a Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound of any of Formula (I), Formula (II), or Formula (III), is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.

Example 9b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of any of Formula (I), Formula (II), or Formula (III), is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.

Example 9c Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix 100 mg of a compound of any of Formula (I), Formula (II), or Formula (III), with 420 mg of powdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract. The mixture is gently blended and poured into a mold to form a lozenge suitable for buccal administration.

Example 9d Fast-Disintegrating Sublingual Tablet

A fast-disintegrating sublingual tablet is prepared by mixing 48.5% by weigh of a compound of Formula (I), Formula (II), or Formula (III), 44.5% by weight of microcrystalline cellulose (KG-802), 5% by weight of low-substituted hydroxypropyl cellulose (50 μm), and 2% by weight of magnesium stearate. Tablets are prepared by direct compression (AAPS Pharm Sci Tech. 2006; 7(2):E41). The total weight of the compressed tablets is maintained at 150 mg. The formulation is prepared by mixing the amount of compound of Formula (I) with the total quantity of microcrystalline cellulose (MCC) and two-thirds of the quantity of low-substituted hydroxypropyl cellulose (L-HPC) by using a three dimensional manual mixer (lnversina®, Bioengineering AG, Switzerland) for 4.5 minutes. All of the magnesium stearate (MS) and the remaining one-third of the quantity of L-HPC are added 30 seconds before the end of mixing.

Example 9e Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of any of Formula (I), Formula (II), or Formula (III), is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.

Example 9f Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound of any of Formula (I), Formula (II), or Formula (III), is mixed with 2.5 g of methylcelluose (1500 mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purified water. The resulting gel mixture is then incorporated into rectal delivery units, such as syringes, which are suitable for rectal administration.

Example 9g Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of a compound of any of Formula (I), Formula (II), or Formula (III), is mixed with 1.75 g of hydroxypropyl celluose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topicl administration.

Example 9h Ophthalmic Solution Composition

To prepare a pharmaceutical opthalmic solution composition, 100 mg of a compound of any of Formula (I), Formula (II), or Formula (III), is mixed with 0.9 g of NaCl in 100 mL of purified water and filterd using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.

Example 9i Nasal Spray Solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compound of any of Formula (I), Formula (II), or Formula (III), is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 μl of spray for each application.

Example 9j Enema Solution

To prepare a pharmaceutical enema, mix 10 mL of 95% ethanol, 40 mL of propylene glycol, and 1.5 mL of benzyl alcohol; add 500 mg of any of Formula (I), Formula (II), or Formula (III) and mix until dissolved. Add 4.2 gm of HPMC and mix until well dispersed. Mix 0.1 gm of benzoic acid and 4.9 gm of sodium benzoate in about 40 mL of purified water. Mix together the two solutions, add an additional 60 mL of water and allow to thicken by standing.

The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims. 

1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein, R¹, R², R³, and R⁴ each are independently selected from H, halogen, —CN, —NO₂, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —C(═O)R¹², —OC(═O)R¹², —CO₂R¹³, —OCO₂R¹², —N(R¹³)₂, —C(═O)N(R¹³)₂, —OC(═O)N(R¹³)₂, —NHC(═O)R¹², —NHC(═O)OR¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, optionally substituted phenyl, and an optionally substituted monocyclic heteroaryl; R⁵ is L⁵-X⁵; L⁵ is —C₁-C₆alkyl-, —C₁-C₆flouroalkyl-, or —C₃-C₆cycloalkyl-, —C₁-C₆alkyl-(optionally substituted aryl)-, —C₁-C₆alkyl-(optionally substituted heteroaryl)-, an an optionally substituted aryl, or an optionally substituted heteroaryl; X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OH, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂; R⁶ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, —C₁-C₆alkyl-(optionally substituted cycloalkyl), —C₁-C₆alkyl- (optionally substituted heterocycloalkyl), —C₁-C₆alkyl-(optionally substituted aryl), or —C₁-C₆alkyl-(optionally substituted heteroaryl); R⁷ is L⁷-X⁷; L⁷ is C₁-C₆alkyl, C₁-C₆fluoroalkyl, or an optionally substituted C₃-C₆cycloalkyl; X⁷ is —CO₂H, —CO₂R¹², —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OH, —OR¹², —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂; each R⁸ and R⁹ is independently selected from H, C₁-C₄alkyl, and C₁-C₄haloalkyl; or two R⁸ groups are taken together with the carbon atom to which they are attached to form a carbonyl (—C(═O)—); or both R⁹ groups are taken together with the carbon atom to which they are attached to form a carbonyl (—C(═O)—); R¹⁰ is H, C₁-C₄alkyl, C₁-C₄haloalkyl, or —L¹⁰-X¹⁰; L¹⁰- is —C₁-C₆alkyl-, —C₃-C₆cycloalkyl-, —C₁-C₆alkyl-(optionally substituted aryl)- or —C₁-C₆alkyl-(optionally substituted heteroaryl)-; X¹⁰ is —CO₂R¹³, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —C(═O)NH—OH, —C(═O)NH—CN, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —NHC(═O)OR¹², —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², —N(R¹³)₂, —C(═O)NHC(═O)R¹², —SO₂NHC(═O)R¹², —SO₂NHC(═O)N(R¹³)₂, or —C(═NR¹⁴)N(R¹³)₂; R¹² is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted benzyl or optionally substituted heteroaryl; each R¹³ is independently selected from H, C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted benzyl, and an optionally substituted heteroaryl; two R¹³ groups attached to the same N atom are taken together with the N atom to which they are attached to form an optionally substituted heterocycloalkyl; R¹⁴ is selected from among H, —S(═O)₂R¹², —S(═O)₂NH₂, —C(═O)R¹², —CN, and —NO₂; m is 1, 2, or
 3. 2. The compound of claim 1, wherein: each R⁸ and R⁹ is each independently selected from H, and —CH₃; or two R⁸ groups are taken together with the carbon atom to which they are attached to form a carbonyl(-C(═O)—); or both R⁹ groups are taken together with the carbon atom to which they are attached to form a carbonyl(-C(═O)—); m is 1 or
 2. 3. The compound of claim 1, wherein: R¹, R², R³, and R⁴ each are independently selected from H, halogen, —CN, —OH, —OR¹³, —S(═O)₂C₁-C₆alkyl, —S(═O)₂N(R¹³)₂, —NHS(═O)₂R¹², —OC(═O)R¹², —C(═O)N(R¹³)₂, —NHC(═O)R¹², C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, C₁-C₄alkoxy, and C₁-C₄heteroalkyl.
 4. The compound of claim 3, wherein: R⁶ is an optionally substituted C₃-C₁₀cycloalkyl, an optionally substituted C₂-C₁₀heterocycloalkyl, an optionally substituted phenyl, an optionally substituted napthyl, an optionally substituted monocyclic heteroaryl containing 0-3 N atoms.
 5. The compound of claim 4, wherein: L⁵ is —C₁-C₆alkyl, or an optionally substituted —C₁-C₆alkyl-phenyl; and X⁵ is F, —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, tetrazolyl, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —OR¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹², or —N(R¹³)₂; L⁷ is C₁-C₆alkyl, C₁-C₆ fluoroalkyl, or an optionally substituted C₃-C₆cycloalkyl; X⁷ is —CO₂R¹³, —C(═O)N(R¹³)₂, tetrazolyl, —OH, or —C(═O)NHC(═O)R¹².
 6. (canceled)
 7. The compound of claim 5, wherein: R¹, R², R³, and R⁴ each are independently selected from H, halogen, —CN, —OH, —S(═O)₂C₁-C₆alkyl, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, C₁-C₄alkoxy, and C₁-C₄heteroalkyl. R⁶ is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted monocyclic heteroaryl containing 0-3 N atoms.
 8. (canceled)
 9. The compound of claim 7, wherein: L⁵ is C₁-C₆alkyl; X⁵ is —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹³)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —OR¹³, —SR¹², —S(═O)₂R¹², or —N(R¹³)₂. L⁷ is C₁-C₆alkyl; X⁷ is CO₂H, —CO₂(C₁-C₄alkyl), or —OH.
 10. The compound of claim 9, wherein: R¹⁰ is H or C₁-C₄alkyl.
 11. The compound of claim 10, wherein: each of R⁸ and R⁹ is H.
 12. (canceled)
 13. (canceled)
 14. The compound of claim 1 having the structure of Formula (II), or a pharmaceutically acceptable salt thereof:


15. (canceled)
 16. The compound of claim 1 having the structure of Formula (III), or a pharmaceutically acceptable salt thereof:


17. The compound of claim 16, wherein: L⁵ is C₁-C₆alkyl; X⁵ is —CO₂R¹³, —CN, —C(═O)NHSO₂R¹², —C(═O)N(R¹³)₂, —NHS(═O)₂R¹², —S(═O)₂N(R¹⁵)₂, —NR¹³S(═O)₂R¹², —NHC(═O)R¹², —OH, —OR¹³, —SR¹², —S(═O)₂R¹², or —N(R¹³)₂. L⁷ is C₁-C₆alkyl; X⁷ is CO₂H, —CO₂(C₁-C₄alkyl), or —OH; R¹⁰ is H or —CH₃.
 18. The compound of claim 17, wherein: X⁵ is —CO₂R¹³, —CN, —C(═O)N(R¹³)₂, or —OH.
 19. The compound of claim 18, wherein: R¹, R², R³, and R⁴ each are independently selected from H, F, Cl, Br, I, —CN, —OH, —OCH₃, —S(═O)₂CH₃, —CH₃, and —CF₃; R¹⁰ is H.
 20. The compound of claim 19, wherein: R⁶ is an optionally substituted phenyl.
 21. The compound of claim 1 selected from among: {3-[Carboxymethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-acetic acid (Compound 1-1); {(4-Fluoro-benzenesulfonyl)-[9-(3-hydroxy-3-methyl-butyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino}-acetic acid (Compound 1-2); 3-{3-[(4-Fluoro-benzenesulfonyl)-(2-hydroxy-2-methyl-propyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionic acid (Compound 1-3); 4-FluoroN-[9-(3-hydroxy-3-methyl-butyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N-(2-hydroxy-2-methyl-propyl)-benzenesulfonamide (Compound 1-4); 3-{3-[Carbamoylmethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionic acid (Compound 1-5); and 3-{3-[Carboxymethyl-(4-fluoro-benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-carbazol-9-yl}-propionic acid (Compound 1-6); or a pharmaceutically acceptable salt thereof.
 22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable inactive ingredient selected from pharmaceutically acceptable diluents, pharmaceutically acceptable excipients, and pharmaceutically acceptable carriers.
 23. (canceled)
 24. (canceled)
 25. (canceled)
 26. (canceled)
 27. (canceled)
 28. (canceled)
 29. (canceled)
 30. (canceled)
 31. A method for treating PGD₂-dependent or PGD₂-mediated disease or condition in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim
 1. 32. The method of claim 31, wherein the PGD₂-dependent or a PGD₂-mediated disease or condition is selected from asthma, rhinitis, allergic conjuctivitis, atopic dermatitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, wound healing, endotoxic shock, pain, inflammatory conditions, eosinophilic esophagitis, eosinophil-associated gastrointestinal disorders (EGID), idiopathic hypereosinophilic syndrome, otitis, airway constriction, mucus secretion, nasal congestion, increased microvascular permeability and recruitment of eosinophils, urticaria, sinusitis, angioedema, anaphylaxia, chronic cough and Churg Strauss syndrome.
 33. (canceled)
 34. (canceled)
 35. (canceled)
 36. (canceled)
 37. (canceled)
 38. The method of claim 31, wherein the PGD₂-dependent or PGD₂-mediated disease or condition is a respiratory disease or condition, an allergic disease or condition, or an inflammatory disease or condition.
 39. (canceled)
 40. (canceled)
 41. (canceled)
 42. (canceled)
 43. (canceled) 